JP5306987B2 - Bicycloheteroaryl compounds as P2X7 modulators and uses thereof - Google Patents

Abstract

Bicycloheteroaryl compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, traumatic injury, and others.

Description

(Field of Invention)
The present invention relates to novel compounds of bicycloheteroaryls class that can modulate the P2X ₇ receptor activity, and to pharmaceutical compositions containing such compounds. Further, the present invention is using the compounds and pharmaceutical compositions of the present invention, abnormal P2X ₇ state activity is causally related, for example, inflammation-related conditions (rheumatoid arthritis in a mammal, osteoarthritis, Parkinson's disease Cardiovascular conditions, including uveitis, asthma, myocardial infarction, and treatment and prevention of pain syndromes (acute and chronic or neuropathic), traumatic brain injury, acute spinal cord injury, neurodegenerative disorders, inflammatory bowel It relates to methods for preventing and / or treating diseases and including but not limited to autoimmune disorders.

(Background of the Invention)
Cell surface receptors of ATP can be divided into a metabolic regulation type (P2Y / P2U) class and an ion channel type (P2X) class. The metabotropic class belongs to the superfamily of G protein-coupled receptors with seven transmembrane segments. Ion channel type class members (P2X _{1 to} P2X ₆ ) are ligand-gated ion channels and are currently considered to be multi-subunit proteins with two transmembrane domains per subunit (non-patented). Reference 1). P2Z receptors have been distinguished from other P2 receptors mainly in three ways (Non-Patent Document 2; Non-Patent Document 3; Non-Patent Document 4). First, activation of the P2Z receptor results in cell permeabilization as well as internal ionic current. Second, 3′-O- (4-benzoyl) benzoyl ATP (BZATP) is the most effective agonist, and ATP itself is rather less effective. Thirdly, the response is strongly inhibited by extracellular magnesium ions, which has been interpreted as indicating that ATP ⁴ − is an active agonist (Non-patent Document 5).

The seventh member of the P2X receptor family is isolated from a rat cDNA library and exhibits the above three characteristics when expressed in human fetal kidney (HEK293) cells (Non-patent Document 6). This receptor (rP2X ₇ ) therefore corresponds to the P2Z receptor. rP2X ₇ is structurally related to other members of the P2X family, but has a longer cytoplasmic C-terminal domain (35-40% amino acid identity exists in the corresponding region of homology, while others compared in the region from 27 to 20 amino acids, C-terminus is 239 amino acids long with rP2X ₇ receptor). rP2X ₇ receptor, the channel can transmit a small cation, and functions as a cytolytic pore. A short application of ATP (1-2s) opens the channel transiently, as is the case with other P2X receptors. Repeated or sustained application of agonists causes cell permeabilization, reducing extracellular magnesium concentration and enhancing this effect. unique C- terminal domain of rP2X ₇ is required for lytic activity of a cell permeabilization and ATP (Non-Patent Document 6).

P2Z / rP2X ₇ receptor, cell lysis of antigen-presenting cells by cytotoxic T lymphocytes, mitogen-stimulated human T lymphocytes, and participates in the formation of multinucleated giant cells (Non-patent Document 7; Non-Patent Document 8; non Patent Document 9). There is a functional difference between rodents and humans (Non-Patent Document 10). Human macrophage P2X ₇ receptor (P2X ₇₎ is currently being cloned, its functional properties have been measured (Non-Patent Document 11). Compared to rats P2X ₇ receptors, requiring agonists of higher concentrations induced cation selective current of human P2X ₇ in receptor by removal of extracellular magnesium ions, is more enhanced relates agonist removed faster modification Is done. Expression of the chimeric molecule, some differences between the rat and human P2X ₇ receptor by exchanging the C- terminal domain of each receptor protein, suggesting that can be modified.

Certain compounds have been reported to act as P2X ₇ antagonists. For example, Patent Document 1 and Patent Document 2, there adamantane derivative has a therapeutic effect in the treatment of rheumatoid arthritis and psoriasis, discloses that exhibit P2X ₇ antagonistic activity. Similarly, Patent Document 3, there is heterocyclic derivative, a P2X ₇ receptor antagonist, immunosuppressive agent, and that rheumatoid arthritis, asthma, septic shock and atherosclerosis are useful for treating Is disclosed. Finally, Patent Document 4 discloses certain substituted phenyl compounds that exhibit immunosuppressive activity. All references cited individually are hereby incorporated by reference in their entirety.
WO99 / 29660 pamphlet International Publication No. 99/29661 Pamphlet WO99 / 29686 pamphlet International Publication No. 00/71529 Pamphlet Buell et al., Europ. J. et al. Neurosci. 1996, Vol. 8, p. 2221 Buisman et al., Proc. Natl. Acad. Sci. USA, 1988, vol. 85, p. 7988 Cockcroft et al., Nature, 1979, 279, p. 541 Steinberg et al. Biol. Chem. 1987, 262, p. 3118 DiVirgilio, Immunol. Today, 1995, Vol. 16, p. 524 Surprenant et al., Science, 1996, 272, p. 735 Blanchard et al., Blood, 1995, vol. 85, p. 3173 Falzoni et al. Clin. Invest. 95: 1207 (1995) Baricoldi et al., Blood, 1996, Vol. 87, p. 682 Hickman et al., Blood, 1994, 84, p. 2452 Rassendren et al. Biol. Chem. 1997, 272, p. 5482

Thus, therapeutic agents which aberrant P2X ₇ activity to deal with the relevant state as the cause, there is a need for associated methods corresponding pharmaceutical compositions and treatment, the present invention aims can realize their needs and To be satisfied.

(Summary of Invention)
Bicycloaryl derivatives of formula I-XIIj and their pharmaceutical compositions are used to treat and prevent conditions mediated by inflammation (eg arthritis, myocardial infarction, pain syndrome (acute and chronic [neuropathic]), traumatic brain injury, acute spinal cord injury, neurodegenerative disorders, immune dysfunction (but not limited to) such as inflammatory bowel disease and autoimmune disorders, including, treating a condition in a mammal associated with aberrant activity of P2X ₇ receptor Therefore, a useful therapeutic agent is disclosed.

Now, bicycloheteroaryl compounds of the invention were found to be capable of mediating the activity of P2X ₇ receptor. This discovery results in new compounds with therapeutic value. It can also be used for various occurrences or pathologies of inflammation, including but not limited to, rheumatoid arthritis, cardiovascular disease, inflammatory bowel disease, acute, chronic, inflammatory and neuropathic pain, toothache and headache ( Activate compounds of the invention to treat, prevent, ameliorate various conditions in mammals such as migraine, cluster headache and tension headache), other conditions associated with inflammation or immune dysfunction Also provided are pharmaceutical compositions comprising as an ingredient, and their use.

  The compounds of the present invention are also useful in the treatment of inflammatory pain and related hyperalgesia and allodynia. They also include neuropathic pain and related hyperalgesia and allodynia (eg, trigeminal or herpes neuralgia, diabetic neuropathy, burning pain, sympathetic pain and brachial nerve ablation It is also useful for the treatment of afferent block syndromes such as The compounds of the invention are also anti-inflammatory agents for the treatment of arthritis and Parkinson's disease, uveitis, asthma, myocardial infarction, traumatic brain injury, spinal cord injury, neurodegenerative disorders, inflammatory bowel disease and autoimmunity It is also useful as a drug to treat disorders, renal dysfunction, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleep disorders, cognition, depression, anxiety, blood pressure, lipid disorders and atherosclerosis.

In one aspect, the present invention provides in vivo, bicycloheteroaryl compounds capable of modulating the activity of P2X ₇ receptor. In a further aspect, the compounds of the invention can antagonize (suppress or inhibit) the activity of the P2X ₇ receptor, thereby typically presenting a condition associated with abnormal P2X ₇ activity. Can be treated.

  The compounds of the present invention have low toxicity, good absorption, good half-life, good solubility, low protein binding affinity, low drug-drug interactions, low inhibitory activity on HERG channels, low QT prolongation and good metabolism Shows stability.

Accordingly, in a first aspect of the present invention, there is provided a bicycloheteroaryl compounds capable of modulating the activity of P2X ₇ receptors in vivo, of formula (I):

（式中、
ＢおよびＹは、独立して、ＣＲ^２ａおよびＣＲ^２ａＲ^２ｂから選択され；
Ｗ、Ｗ’およびＺは、独立して、ＣＲ^４およびＮから選択されるが、ただし、Ｗ、Ｗ’およびＺの３つ全てが同時にＮであることはなく；
Ｌ^１は、置換または非置換のＣ_１−Ｃ_５アルキレンであり；
ｎは、０、１、２、３、または４であり；
Ｒ^１は、置換または非置換の３〜１３員シクロアルキル環、３〜１３員ヘテロシクロアルキル環、３〜１３員アリール環および３〜１３員ヘテロアリール環から選択され；
Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２’およびＲ^２’’の各々は、独立して、水素、ハロ、および置換または非置換のＣ_１−Ｃ_６アルキルから選択されるか；あるいはＲ^２’およびＲ^２’’のいずれかが一緒になって、３〜７個の原子のシクロアルキル環またはシクロヘテロアルキル環を形成し；
Ｒ^３は、水素あるいはアシル、置換アシル、置換または非置換のアシルアミノ、置換または非置換のアルキルアミノ、置換または非置換のジアルキルアミノ、置換または非置換のアルキルチオ、置換または非置換のアルコキシ、アルコキシカルボニル、置換アルコキシカルボニル、置換または非置換のアルキルアリールアミノ、アリールアルキルオキシ、置換アリールアルキルオキシ、アリール、置換アリール、アリールアルキル、置換または非置換のスルホキシド、置換または非置換のスルホン、置換または非置換のスルファニル、置換または非置換のアミノスルホニル、置換または非置換のアリールスルホニル、硫酸、硫酸エステル、置換または非置換のカルバモイル、シアノ、置換または非置換のシクロアルキル、置換または非置換のシクロヘテロアルキル、ハロ、ヘテロアリールオキシ、置換または非置換のヘテロアリール、置換または非置換のヘテロアルキル、ニトロおよびチオから選択される官能基であるが；ただしＲ^３は、水素結合供与基以外であり；
Ｒ^４は、独立して、Ｈ、アルキル、置換アルキル、アシル、置換アシル、置換または非置換のアシルアミノ、置換または非置換のアルキルアミノ、置換または非置換のアルキルチオ、置換または非置換のアルコキシ、アルコキシカルボニル、置換アルコキシカルボニル、置換または非置換のアルキルアリールアミノ、アリールアルキルオキシ、置換アリールアルキルオキシ、アミノ、アリール、置換アリール、アリールアルキル、置換または非置換のスルホキシド、置換または非置換のスルホン、置換または非置換のスルファニル、置換または非置換のアミノスルホニル、置換または非置換のアリールスルホニル、硫酸、硫酸エステル、置換または非置換のジヒドロキシホスホリル、置換または非置換のアミノジヒドロキシホスホリル、アジド、カルボキシ、置換または非置換のカルバモイル、シアノ、置換または非置換のシクロアルキル、置換または非置換のシクロヘテロアルキル、置換または非置換のジアルキルアミノ、ハロ、ヘテロアリールオキシ、置換または非置換のヘテロアリール、置換または非置換のヘテロアルキル、ヒドロキシ、ニトロおよびチオから選択され；
点線の結合は、単結合または二重結合である）
で表される化合物、あるいはその医薬的に許容し得る塩、溶媒和物またはプロドラッグ、ならびにその立体異性体、同位体改変体および互変異性体を開示する。

(Where
B and Y are independently selected from CR ^2a and CR ^2a R ^2b ;
W, W ′ and Z are independently selected from CR ⁴ and N, provided that all three of W, W ′ and Z are not N at the same time;
L ¹ is a substituted or unsubstituted C ₁ -C ₅ alkylene;
n is 0, 1, 2, 3, or 4;
R ¹ is selected from a substituted or unsubstituted 3-13 membered cycloalkyl ring, 3-13 membered heterocycloalkyl ring, 3-13 membered aryl ring and 3-13 membered heteroaryl ring;
Each of R ^2a , R ^2b , R ^{2 ′} and R ^{2 ″} is independently selected from hydrogen, halo, and substituted or unsubstituted C ₁ -C ₆ alkyl; or R ^{2 ′} and R Any of ^{2 ″} together form a 3-7 atom cycloalkyl or cycloheteroalkyl ring;
R ³ is hydrogen or acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl , Substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted Sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfate ester, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A functional group selected from cycloheteroalkyl, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, nitro and thio; provided that R ³ is other than a hydrogen bond donating group Yes;
R ⁴ is independently H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxy Carbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or Unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfate ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, Carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted hetero Selected from aryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro and thio;
(The dotted bond is a single bond or a double bond)
Or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, isotopic variants and tautomers thereof.

  In a further embodiment, with respect to compounds of formula I, n is 0-4. In another embodiment, n is 0-2. In certain embodiments, n is 1.

In a further embodiment, with respect to compounds of formula I, L ¹ is C ₁ —, which is unsubstituted or substituted with one or more substituents selected from alkyl, oxo, aryl, hydroxyl, or hydroxyalkyl. C ₅ alkylene group.

In a further embodiment, with respect to compounds of formula I, B and Y are independently selected from CR ^2a and CR ^2a R ^2b .

In a further embodiment, with respect to compounds of formula I, B and Y are independently selected from CR ^2a R ^2b and the dotted bond is a single bond.

In a further embodiment, with respect to compounds of formula I, B and Y may all represent CH ₂ and the dotted bond is a single bond.

In a further embodiment, with respect to compounds of formula I, B and Y are independently selected from CR ^2a and the dotted bond is a double bond.

  In a further embodiment, with respect to compounds of formula I, B and Y may all represent CH and the dotted bond is a double bond.

  In a further embodiment, with respect to compounds of formula I, n is 0, 1 or 2. In one particular embodiment, n is 1.

  In another embodiment, with respect to compounds of formula I:

基のＲ^２’およびＲ^２’’の各々は、ＨまたはＭｅである。特定の一実施形態では、Ｒ^２’およびＲ^２’’の各々は、Ｈである。

Each of the radicals R ^{2 ′} and R ^{2 ″} is H or Me. In one particular embodiment, each of R ^{2 ′} and R ^{2 ″} is H.

  In a further embodiment, with respect to compounds of formula I:

基のＲ^２’およびＲ^２’’の一方は、Ｍｅ、Ｅｔ、ハロおよびＣｌから選択されてもよく、他方はＨである。

One of the radicals R ^{2 ′} and R ^{2 ″} may be selected from Me, Et, halo and Cl and the other is H.

In a further embodiment, with respect to compounds of formula I, R ¹ is substituted or unsubstituted aryl. In one particular embodiment, R ¹ is substituted or unsubstituted phenyl.

In a further embodiment, with respect to compounds of formula I, R ¹ is a substituted or unsubstituted cycloalkyl. In another embodiment, R ¹ is substituted or unsubstituted adamantyl. In yet another embodiment, R ¹ is substituted or unsubstituted cyclohexyl or cycloheptyl.

  In a further embodiment, with respect to compounds of formula I, each of W and W 'is N.

In a further embodiment, with respect to compounds of formula I, each of W, Z, and W ′ is CR ⁴ . In one particular embodiment, each of W, Z and W ′ is CH.

In a further embodiment, with respect to compounds of formula I, each of W and Z is CR ⁴ , W ′ is CR ⁵ and R ⁵ is H, alkyl, cycloalkyl or halo. In one embodiment, R ⁵ is halo or alkyl. In certain embodiments, R ⁵ is H or halo. In more specific embodiments, R ⁵ is H, Cl, F, Me, or cyclopropyl.

  In a further aspect, the present invention provides a pharmaceutical composition comprising a bicycloheteroaryl compound of the present invention and a pharmaceutical carrier, excipient or diluent. In this aspect of the invention, the pharmaceutical composition may comprise one or more compounds described herein. Furthermore, all of the compounds of the invention useful in the pharmaceutical compositions and methods of treatment described herein are pharmaceutically acceptable when prepared and used.

  In a further aspect of the invention, the invention relates to, among others, the conditions listed herein, for example, rheumatoid arthritis, osteoarthritis, uveitis, asthma, myocardial infarction, traumatic brain injury; sepsis Predisposed to or suffering from inflammation-related conditions such as septic shock, atherosclerosis, chronic obstructive pulmonary disease (COPD), acute spinal cord injury, inflammatory bowel disease and autoimmune disorders A method of treating a mammal is provided, the method comprising administering an effective amount of one or more of the described pharmaceutical compositions.

In yet some alternative treatment methods, the present invention is abnormal P2X ₇ receptor activity is related conditions cause, for example, either cause pain reaction, or imbalance related condition in the maintenance of basal activity of sensory nerves Methods are provided for treating mammals susceptible to or suffering from. The amine compounds of the present invention can be used in various origins or causes of pain, such as acute pain, inflammatory pain (eg, pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (eg, zonal) Postherpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillain-Barre syndrome, fibromyalgia, phantom limb pain, postmastectomy pain, peripheral neuropathy, HIV neuropathy and chemical treatment induction, Visceral pain (eg, associated with gastroesophageal reflux disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gynecological and urological disorders), toothache and There are uses as analgesics for the treatment of headaches (eg migraine, cluster headache and tension headache).

In a further embodiment of the treatment method, the present invention is the state in which aberrant activity of P2X ₇ receptors are involved as the cause, for example, Parkinson's disease, multiple sclerosis, for example, be mediated by neuronal inflammation, such as traumatic brain injury and encephalitis Diseases and disorders that cause or cause it; for example, neuropsychiatric diseases and disorders through the center, such as manic depression, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognitive disorders; Epilepsy and seizure disorders; eg, urinary incontinence, dysuria, rectal hypersensitivity, fecal incontinence, benign prostatic hyperplasia and prostatic dysfunction such as inflammatory bowel disease, bladder dysfunction and intestinal dysfunction; Respiratory and airway diseases and disorders such as asthma, reactive airway disease and chronic obstructive pulmonary disease; eg, rheumatoid arthritis and Diseases and disorders mediated by or resulting in inflammation such as osteoarthritis, myocardial infarction, various autoimmune diseases and disorders, uveitis and atherosclerosis; itching such as psoriasis / Pruritus; obesity; lipid disorders; cancer; blood pressure; spinal cord injury; and for treating mammals susceptible to or suffering from neurodegenerative diseases and disorders, including cardiovascular and renal dysfunction A method is provided, the method comprising administering an amount of one or more of the described pharmaceutical compositions effective to treat or prevent the condition.

  In a further aspect, the invention provides methods for synthesizing the compounds of the invention, and representative synthetic procedures and pathways are described later herein.

Thus, the main object of the present invention is a novel that can alter the activity of the P2X ₇ receptor and thus avoid or treat any disease whose cause may be related to the activity of the P2X ₇ receptor. It is to provide a series of compounds.

A further object of the present invention, the activation of P2X ₇ receptors may be related causally to a disease or condition, such as pain and inflammation, to provide a series of compounds which may be treated or alleviated.

  Further objects of the invention relate to the central nervous system, cardiovascular conditions, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and other diseases where inflammatory reactions are present It is to provide a pharmaceutical composition effective for treating or preventing various disease states including diseases.

  Other objects and advantages will become apparent to those skilled in the art upon consideration of the following detailed description.

(Detailed description of the invention)
(Definition)
When describing a compound, a pharmaceutical composition comprising the compound, and methods for using the compound and composition, the following terms have the following meanings, unless otherwise indicated. It should also be understood that any of the moieties described below may be substituted with various substituents, and that each definition includes such substituted moieties within their scope. . By way of non-limiting example, such substituents include, for example, halo (eg, fluoro, chloro, bromo), —CN, —CF ₃ , —OH, —OCF ₃ , C ₂ -C ₆ alkenyl, C Examples include _3- C ₆ alkynyl, C ₁ -C ₆ alkoxy, aryl and di-C ₁ -C ₆ alkylamino. Further, it should be understood herein that the terms “group” and “radical” are considered interchangeable.

“Acyl” is a radical: —C (O) R ^20, where R ²⁰ is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, as defined herein, Heteroaryl and heteroarylalkyl). Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

“Acylamino” refers to the radical —NR ²¹ C (O) R ^22, where R ²¹ is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, hetero, as defined herein. Alkyl, heteroaryl, heteroarylalkyl, and R ²² is hydrogen, alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl or heteroarylalkyl). Representative examples include, but are not limited to formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethylcarbonylamino, benzoylamino, benzylcarbonylamino, and the like.

“Acyloxy” refers to the group —OC (O) R ^23, where R ²³ is hydrogen, alkyl, aryl, or cycloalkyl.

“Substituted alkenyl” is intended to include the groups mentioned in the definition of “substituted” herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, Aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, One or more substituents selected from the group consisting of thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) _2-, and aryl-S (O) _2- ; For example 1 to 5 substituents, in particular 1 Refers to an alkenyl having 3 substituents.

“Alkoxy” refers to the group —OR ^24, where R ²⁴ is alkyl. Specific alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy and the like. .

“Substituted alkoxy” is intended to include the groups mentioned in the definition of “substituted” herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, Aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy One or more selected from the group consisting of: thioketo, thiol, alkyl-S (O) —, aryl-S (O) —, alkyl-S (O) ₂ — and aryl-S (O) ₂ — Substituents, eg 1-5 In particular, an alkoxy group having 1 to 3 substituents.

“Alkoxycarbonylamino” refers to the group —NR ²⁵ C (O) OR ^26, where R ²⁵ is hydrogen, alkyl, aryl, or cycloalkyl, and R ²⁶ is alkyl or cycloalkyl. .

  “Alkyl” is in particular lower alkyl having up to about 11 carbon atoms, more specifically 1-8 carbon atoms, and even more specifically having 1-6 carbon atoms. A monovalent saturated alkane radical group. The hydrocarbon chain may be linear or branched. This term is typified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like. The term “lower alkyl” refers to an alkyl group having 1 to 6 carbon atoms. The term “alkyl” also includes “cycloalkyl” as defined below.

“Substituted alkyl” is intended to include the groups mentioned in the definition of “substituted” herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, Aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, heteroaryl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy , thioketo, thiol, alkyl -S (O) -, aryl -S (O) -, alkyl -S _{(O) 2} - and aryl -S _{(O) 2} - 1 or more substituents selected from the group consisting of Group, eg 1-5 positions A substituent, particularly an alkyl group having 1 to 3 substituents.

"Alkylene" is a divalent saturated alkene radical group having 1 to 11 carbon atoms, more specifically 1 to 6 carbon atoms, which may be straight or branched. Say. The term includes methylene (—CH ₂ —), ethylene (—CH ₂ CH ₂ —), propylene isomers (eg, —CH ₂ CH ₂ CH ₂ — and —CH (CH ₃ ) CH ₂ —), and the like. Represented by the basic group.

“Substituted alkylene” is intended to include those groups mentioned in the definition of “substituted” herein, and in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, Aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azide, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O )-, Aryl-S (O)-, alkyl-S (O) _2-, and aryl-S (O) _2-, one or more substituents, for example 1-5 substituents In particular, an alkylene group having 1 to 3 substituents Yeah.

“Alkenyl” is a monovalent olefinically unsaturated hydrocarbyl group preferably having 2 to 11 carbon atoms, in particular 2 to 8 carbon atoms, more specifically 2 to 6 carbon atoms. It may be linear or branched, and refers to a group in which at least one, particularly 1-2 sites are olefinically unsaturated. Specific alkenyl groups include ethenyl (—CH═CH ₂ ), n-propenyl (—CH ₂ CH═CH ₂ ), isopropenyl (—C (CH ₃ ) ═CH ₂ ), vinyl, saturated vinyl, and the like. It is done.

“Alkenylene” is a divalent olefinically unsaturated hydrocarbyl group having in particular up to about 11 carbon atoms, more specifically 2 to 6 carbon atoms, which may be straight-chained or branched It may be a chain and refers to a group in which at least one, particularly 1-2 sites, are olefinically unsaturated. The term includes ethenylene (—CH═CH—), propenylene isomers (eg, —CH═CHCH ₂ —, —C (CH ₃ ) ═CH— and —CH═C (CH ₃ ) —) and the like. Represented by the group.

“Alkynyl” is an acetylenic or alkyne unsaturated hydrocarbyl group having in particular 2 to 11 carbon atoms, more particularly 2 to 6 carbon atoms, which may be linear or branched. It may be branched and refers to a group in which at least one, especially 1-2, sites are alkynyl unsaturated. Specific non-limiting examples of alkynyl groups include acetylene, ethynyl (—C≡CH), propargyl (—CH ₂ C≡CH), and the like.

“Substituted alkynyl” is intended to include the groups mentioned in the definition of “substituted” herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, Aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, One or more substituents selected from the group consisting of thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) _2-, and aryl-S (O) _2- , for example 1 to 5 substituents, especially 1 An alkynyl group having three substituents.

As used herein, “alkanoyl” or “acyl” refers to the group R ²⁷ —C (O) —, where R ²⁷ is hydrogen or alkyl, as defined above.

  “Aryl” refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include asanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene. , Naphthalene, octacene, octaphen, octalene, octalene, obalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preaden, pyrene, pyranthrene, rubicine, triphenylene, trinaphthalene, etc. Group, but is not limited thereto. In particular, the aryl group contains 6 to 14 carbon atoms.

“Substituted aryl” is intended to include the groups mentioned in the definition of “substituted” herein, in particular acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, substituted alkyl. , Alkynyl, substituted alkynyl, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, thioalkoxy, substituted 1 selected from the group consisting of thioalkoxy, thioaryloxy, thiol, alkyl-S (O)-, aryl-S (O)-, alkyl-S (O) _2-, and aryl-S (O) _2-. More than one substituent For example, an aryl group which may be optionally substituted with 1 to 5 substituents, particularly 1 to 3 substituents.

  “Fused aryl” refers to an aryl having two ring carbons shared with a second aryl or aliphatic ring.

  “Alkaryl” refers to an aryl group, as defined above, substituted with one or more alkyl groups, as defined above.

  “Aralkyl” or “arylalkyl” refers to an alkyl group, as defined above, that is substituted with one or more aryl groups, as defined above.

  “Aryloxy” refers to the group —O-aryl, where “aryl” is as defined above.

“Alkylamino” refers to the group alkyl-NR ²⁸ R ^29, where R ²⁸ and R ²⁹ are each independently selected from hydrogen and alkyl.

“Arylamino” refers to the group aryl-NR ³⁰ R ^31, where R ³⁰ and R ³¹ are each independently selected from hydrogen, aryl and heteroaryl.

“Alkoxyamino” refers to the radical —N (H) OR ³² where R ³² is an alkyl or cycloalkyl group as defined herein.

  “Alkoxycarbonyl” refers to the radical —C (O) -alkoxy where alkoxy is as defined herein.

“Alkylarylamino” refers to the radical —NR ³³ R ^34, where R ³³ represents an alkyl or cycloalkyl group, and R ³⁴ is aryl, as defined herein.

“Alkylsulfonyl” refers to the radical —S (O) ₂ R ^35, where R ³⁵ is an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.

“Alkylsulfinyl” refers to the radical —S (O) R ^35, where R ³⁵ is an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl and the like.

“Alkylthio” refers to the radical —SR ^35, where R ³⁵ is an alkyl or cycloalkyl group as defined herein, which, as appropriate, is defined herein. May be substituted. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio and the like.

“Amino” refers to the radical: —NH ₂ .

As used herein, “substituted amino” is intended to include the groups listed in the definition of “substituted” herein, and in particular the group: —N (R ³⁶ ) ₂ (wherein each R ³⁶ is independently Selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, or both R groups together form an alkylene group. Forming). When both R groups are hydrogen, —N (R ³⁶ ) ₂ is an amino group.

“Aminocarbonyl” refers to the group —C (O) NR ³⁷ R ³⁷ where each R ³⁷ is independently hydrogen, alkyl, aryl or cycloalkyl, or the R ³⁷ groups are taken together. Forming an alkylene group.

“Aminocarbonylamino” refers to the group —NR ³⁸ C (O) NR ³⁸ R ³⁸ where each R ³⁸ is independently hydrogen, alkyl, aryl, or cycloalkyl, or two R Group together form an alkylene group).

“Aminocarbonyloxy” refers to the group —OC (O) NR ³⁹ R ^39, where each R ³⁹ is independently hydrogen, alkyl, aryl or cycloalkyl, or both R groups together To form an alkylene group.

  “Arylalkyloxy” refers to an —O-arylalkyl radical where arylalkyl is as defined herein.

“Arylamino” refers to the radical —NHR ^40, where R ⁴⁰ represents an aryl group as defined herein.

  “Aryloxycarbonyl” refers to the radical —C (O) —O-aryl, where aryl is as defined herein.

“Arylsulfonyl” refers to the radical —S (O) ₂ R ^41, where R ⁴¹ is an aryl or heteroaryl group as defined herein.

“Azide” refers to the radical —N ₃ .

  “Bicycloaryl” refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system. Representative bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. In particular, the aryl group contains 8 to 11 carbon atoms.

  “Bicycloheteroaryl” refers to a monovalent bicycloheteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent bicycloheteroaromatic ring system. Typical bicycloheteroaryl groups include benzofuran, benzimidazole, benzindazole, benzdioxane, chromene, chroman, cinnoline, phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, benzoin. Groups derived from thiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolidine, quinoxaline, benzomorphane, tetrahydroisoquinoline, tetrahydroquinoline, etc. For example, but not limited to. Preferably, the bicycloheteroaryl group is 9-11 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred. Particular bicycloheteroaryl groups are groups derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.

“Carbamoyl” is a radical: —C (O) N (R ⁴² ) _2, wherein each R ⁴² group is independently hydrogen, alkyl, cycloalkyl, or aryl, as defined herein, These may optionally be substituted as defined herein).

  “Carboxy” refers to the radical —C (O) OH.

  “Carboxyamino” refers to the radical —N (H) C (O) OH.

  “Cycloalkyl” is a cyclic hydrocarbyl group having from 3 to about 10 carbon atoms and having a plurality of fused rings, including single or fused ring systems and bridged ring systems, optionally containing 1 to 1 A group that may be substituted with three alkyl groups. Such cycloalkyl groups include, for example, monocyclic systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl and the like, and multiples such as adamantaneyl. Examples thereof include a ring structure.

“Substituted cycloalkyl” is intended to include those groups mentioned in the definition of “substituted” herein, and in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino Aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo One or more substituents selected from the group consisting of: thiol, alkyl-S (O) —, aryl-S (O) —, alkyl-S (O) ₂ — and aryl-S (O) ₂ — For example 1 to 5 substituents, in particular A cycloalkyl group having 1 to 3 substituents.

“Cycloalkoxy” refers to the group —OR ^43, where R ⁴³ is cycloalkyl. Examples of the cycloalkoxy group include cyclopentoxy, cyclohexoxy and the like.

  “Cycloalkenyl” has 3 to 10 carbon atoms and has a plurality of fused rings, including single or fused ring systems and bridged ring systems, and has at least one, in particular 1-2 sites. Refers to a cyclic hydrocarbyl group that is olefinically unsaturated. Examples of the cycloalkenyl group include monocyclic systems such as cyclohexenyl, cyclopentenyl, cyclopropenyl and the like.

“Substituted cycloalkenyl” is intended to include the groups mentioned in the definition of “substituted” herein, in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino Aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo One or more substituents selected from the group consisting of: thiol, alkyl-S (O) —, aryl-S (O) —, alkyl-S (O) ₂ — and aryl-S (O) ₂ — E.g. 1 to 5 substituents, In particular, it refers to a cycloalkenyl group having 1 to 3 substituents.

  A “fused cycloalkenyl” has two carbon atoms shared by a second aliphatic or aromatic ring and has an olefinic unsaturation arranged to impart aromaticity to the cycloalkenyl ring Refers to cycloalkenyl.

  “Cyanato” refers to the radical —OCN.

  “Cyano” refers to the radical —CN.

“Dialkylamino” refers to the radical —NR ⁴⁴ R ^45, where R ⁴⁴ and R ⁴⁵ are independently alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl as defined herein. Represents a cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or substituted heteroaryl group).

  “Ethenyl” refers to substituted or unsubstituted — (C═C) —.

  “Ethylene” refers to substituted or unsubstituted — (C—C) —.

  “Ethynyl” refers to — (C≡C) —.

  “Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo. Preferred halo groups are fluoro or chloro.

  “Hydroxy” refers to the radical: —OH.

“Nitro” refers to the radical: —NO ₂ .

“Substituted” refers to a group in which each of one or more hydrogen atoms is independently replaced with the same or different substituent (s). ^{Representative substituents, -X, -R 46, -O -} , = O, -OR 46, -SR 46, -S -, = S, -NR 46 R 47, = NR 46, -CX 3 _{, -CF 3, -CN, -OCN,} -SCN, -NO, -NO 2, = N 2, -N 3, -S (O) 2 O -, -S (O) 2 OH, -S (O ) ₂ R ⁴⁶ , —OS (O ₂ ) O ⁻ , —OS (O) ₂ R ⁴⁶ , —P (O) (O ⁻ ) ₂ , —P (O) (OR ⁴⁶ ) (O ⁻ ), —OP (O) (OR ⁴⁶ ) (OR ⁴⁷ ), —C (O) R ⁴⁶ , —C (S) R ⁴⁶ , —C (O) OR ⁴⁶ , —C (O) NR ⁴⁶ R ⁴⁷ , —C (O ^{) O -, -C (S)} OR 46, -NR 48 C (O) NR 46 R 47, -NR 48 C (S) NR 46 R 47, -NR 49 C (NR 48) NR In ⁶ R ⁴⁷ and ^{-C (NR 48) NR 46 R} 47 ( wherein each X is independently a ^{halogen; R 46, R 47, R} 48 and ^{R 49} are each independently hydrogen, Alkyl, substituted alkyl, aryl, substituted alkyl, arylalkyl, substituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted Heteroarylalkyl, —NR ⁵⁰ R ⁵¹ , —C (O) R ⁵⁰ or —S (O) ₂ R ⁵⁰ , or optionally R ⁵⁰ and R ⁵¹ together with the atoms to which they are attached become, form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ⁵⁰ Contact Fine R ⁵¹ is independently hydrogen, alkyl, substituted alkyl, aryl, substituted alkyl, arylalkyl, substituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl Aryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl), but is not limited thereto.

  Examples of representative substituted aryl include:

が挙げられる。

Is mentioned.

In these formulas, one of R ⁵² and R ⁵³ is hydrogen, and at least one of R ⁵² and R ⁵³ is each independently alkyl, alkenyl, alkynyl, cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, hetero aryloxy, alkylamino, arylamino, ^{heteroarylamino, NR 54 COR 55, NR 54} SOR 55, NR 54 SO 2 R 57, COO -alkyl, COO ^{aryl, CONR 54 R 55, CONR 54} OR 55, NR 54 R 55 , _SO 2 ^NR 54 ^R 55, S- alkyl, S- alkyl, SO-alkyl, SO ₂ alkyl, S aryl, SO aryl is selected from SO ₂ aryl; or ^{R 52} and ^{R 53,} taken together, must Depending on N, O and Form a ring of 5-8 atoms (saturated or unsaturated) containing one or more heteroatoms selected from the group of S. R ⁵⁴ , R ⁵⁵ and R ⁵⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl, substituted aryl, heteroaryl, substituted alkyl or heteroalkyl, and the like.

  “Hetero” when used to describe a compound or group present on a compound means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen or sulfur heteroatoms. means. Hetero may apply to any of the hydrocarbyl groups described above, for example, alkyl having 1-5, especially 1-3 heteroatoms, such as heteroalkyl, cycloalkyl, such as cycloheteroalkyl. , Aryl, such as heteroaryl, cycloalkenyl, cycloheteroalkenyl and the like.

  “Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Representative heteroaryl groups include acridine, arsindole, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, Isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline Quinolidine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, thisanthin Guide is the group including but not limited to. A 5- to 15-membered heteroaryl group is preferred, and a 5- to 10-membered heteroaryl group is particularly preferred. Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

  Representative examples of heteroaryl include the following:

が挙げられ、各Ｙは、カルボニル、Ｎ、ＮＲ^５８、ＯおよびＳから選択され；Ｒ^５８は、独立して、水素、アルキル、シクロアルキル、シクロヘテロアルキル、アリール、ヘテロアリール、ヘテロアルキルなどである。

Each Y is selected from carbonyl, N, NR ⁵⁸ , O and S; R ⁵⁸ is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl, and the like is there.

  The term “cycloheteroalkyl” as used herein refers to stable heterocyclic non-aromatic and fused rings containing one or more heteroatoms independently selected from N, O and S. . A fused heterocyclic ring system may contain carbocycles and need only contain one heterocycle. Examples of heterocycles include piperazinyl, homopiperazinyl, piperidinyl and morpholinyl, the following:

の例示的な例で示されるが、これらに限定されず、式中、各Ｘは、ＣＲ^５８ _２、ＮＲ^５８、ＯおよびＳから選択され；各Ｙは、ＮＲ^５８、ＯおよびＳから選択され；Ｒ^５８は、独立して、水素、アルキル、シクロアルキル、シクロヘテロアルキル、アリール、ヘテロアリール、ヘテロアルキルなどである。これらのシクロヘテロアルキル環は、必要に応じて、アシル、アシルアミノ、アシルオキシ、アルコキシ、置換アルコキシ、アルコキシカルボニル、アルコキシカルボニルアミノ、アミノ、置換アミノ、アミノカルボニル、アミノカルボニルアミノ、アミノカルボニルオキシ、アリール、アリールオキシ、アジド、カルボキシル、シアノ、シクロアルキル、置換シクロアルキル、ハロゲン、ヒドロキシル、ケト、ニトロ、チオアルコキシ、置換チオアルコキシ、チオアリールオキシ、チオケト、チオール、アルキル−Ｓ（Ｏ）−、アリール−Ｓ（Ｏ）−、アルキル−Ｓ（Ｏ）_２−およびアリール−Ｓ（Ｏ）_２−からなる群から選択される１個以上の基で置換されている。置換する基としては、カルボニルまたはチオカルボニルが挙げられ、これらは、例えば、ラクタムおよび尿素誘導体を提供する。

Although not limited to these examples, each X is selected from CR ⁵⁸ ₂ , NR ⁵⁸ , O and S; each Y is selected from NR ⁵⁸ , O and S R ⁵⁸ is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl, and the like. These cycloheteroalkyl rings are optionally acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryl Oxy, azide, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O)-, aryl-S ( Substituted with one or more groups selected from the group consisting of O)-, alkyl-S (O) _2-, and aryl-S (O) _2- . Substituting groups include carbonyl or thiocarbonyl, which provide, for example, lactam and urea derivatives.

  Representative examples of cycloheteroalkenyl include the following:

が挙げられ、各Ｘは、ＣＲ^５８ _２、ＮＲ^５８、ＯおよびＳから選択され；各Ｙは、カルボニル、Ｎ、ＮＲ^５８、ＯおよびＳから選択され；Ｒ^５８は、独立して、水素、アルキル、シクロアルキル、シクロヘテロアルキル、アリール、ヘテロアリール、ヘテロアルキルなどである。

Each X is selected from CR ⁵⁸ ₂ , NR ⁵⁸ , O and S; each Y is selected from carbonyl, N, NR ⁵⁸ , O and S; R ⁵⁸ is independently hydrogen, Alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl and the like.

  Examples of representative aryls having heteroatoms containing substitution include the following:

が挙げられ、各Ｘは、ＣＲ^５８ _２、ＮＲ^５８、ＯおよびＳから選択され；各Ｙは、カルボニル、ＮＲ^５８、ＯおよびＳから選択され；Ｒ^５８は、独立して、水素、アルキル、シクロアルキル、シクロヘテロアルキル、アリール、ヘテロアリール、ヘテロアルキルなどである。

Each X is selected from CR ⁵⁸ ₂ , NR ⁵⁸ , O and S; each Y is selected from carbonyl, NR ⁵⁸ , O and S; R ⁵⁸ is independently hydrogen, alkyl, Cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl and the like.

"Hetero substituent", A compound of the present invention, B, W, as the R ⁴ in R ^{4 C} group present as a group substituting directly to the Y or Z or a "substituted" in the compound, aryl and A halo atom-containing functional group, an O atom-containing functional group, an S atom-containing functional group, or an N atom-containing functional group, which may be present as a substituent in the aliphatic group. Examples of hetero substituents include
-Halo,
^{_{-NO 2, -NH 2, -NHR 59}} , -N (R 59) 2,
_{^{-NRCOR, -NR 59 SOR 59, -NR}} 59 SO 2 R 59, OH, CN,
-CO ₂ H,
^{-R 59 -OH, -O-R 59} , -COOR 59,
_{^{-CON (R 59) 2, -CONROR}} 59,
_{^{-SO 3 H, -R 59 -S,}} -SO 2 N (R 59) 2,
-S (O) R ⁵⁹ , -S (O) ₂ R ⁵⁹
Wherein each R ⁵⁹ is independently aryl or aliphatic and is optionally substituted. Of the hetero substituents containing R ⁵⁹ groups, those containing aryl and alkyl R ⁵⁹ groups as defined herein are preferred. Preferred hetero substituents are those listed above.

A “hydrogen bond donating” group refers to a group comprising an OH or NH function. Examples of “hydrogen bond donating” groups include —OH, —NH ₂ and —NH—R ^59a, where R ^59a is alkyl, acyl, cycloalkyl, aryl or heteroaryl.

“Dihydroxyphosphoryl” refers to the radical —PO (OH) ₂ .

  “Substituted dihydroxyphosphoryl” includes the groups listed in the definition of “substituted” herein, in particular a dihydroxyphosphoryl radical in which one or two hydroxyl groups are substituted. Say. Suitable substituents are described in detail below.

“Aminohydroxyphosphoryl” refers to the radical: —PO (OH) NH ₂ .

  “Substituted aminohydroxyphosphoryl” is intended to include the groups mentioned in the definition of “substituted” herein, in particular aminohydroxyphosphoryl, wherein the amino group is substituted with one or two substituents. Say what you are. Suitable substituents are described in detail below. In certain embodiments, the hydroxyl group can also be substituted.

“Thioalkoxy” refers to the group —SR ^60, where R ⁶⁰ is alkyl.

“Substituted thioalkoxy” is intended to include the groups mentioned in the definition of “substituted” herein, and in particular acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino Aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo One or more substituents selected from the group consisting of: thiol, alkyl-S (O) —, aryl-S (O) —, alkyl-S (O) ₂ — and aryl-S (O) ₂ — For example 1 to 5 substituents, in particular It refers to a thioalkoxy group having 1 to 3 substituents.

  “Sulfanyl” refers to the radical HS—. “Substituted sulfanyl” refers to a radical such as RS—, where R is any substituent described herein.

“Sulfonyl” refers to the divalent radical —S (O ₂ ) —. “Substituted sulfonyl” refers to a radical such as R ⁶¹ — (O ₂ ) S—, wherein R ⁶¹ is any substituent described herein. “Aminosulfonyl” or “sulfonamide” refers to the radical: H ₂ N (O ₂ ) S—, where “substituted aminosulfonyl” or “substituted sulfonamide” is R ⁶² ₂ N (O ₂ ) S— (where Each R ⁶² is independently a radical such as any substituent described herein.

“Sulfone” refers to the group —SO ₂ R ⁶³ . In certain embodiments, R ⁶³ is selected from H, lower alkyl, alkyl, aryl and heteroaryl.

“Thioaryloxy” refers to the group —SR ⁶⁴ where R ⁶⁴ is aryl.

  “Thioketo” refers to the group: ═S.

  “Thiol” refers to the group —SH.

  Those skilled in the art of organic synthesis know that the maximum number of heteroatoms in a stable and chemically possible heterocycle (whether aromatic or non-aromatic) is the size of the ring, the degree of unsaturation and the heteroatom's You will recognize that it is determined by the valence. In general, the heterocycle may have 1 to 4 heteroatoms as long as the heteroaromatic ring is chemically possible and stable.

  “Pharmaceutically acceptable” is recognized by federal or state regulatory agencies or by other commonly recognized pharmacopoeias for use in the United States Pharmacopeia or animals, particularly humans. It means that it is enumerated.

  “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is pharmaceutically acceptable and has the desired pharmacological activity of the compound of the invention. Such salts include: (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclohexane Pentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor Sulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 3 Acid addition salts formed with phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucoic acid, etc .; or (2) present in the parent compound Acidic protons are replaced by metal ions such as alkali metal ions, alkaline earth ions or aluminum ions, or coordinate with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Included are salts that are sometimes formed. Further, salts include, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and if the compound contains a basic functional group, a salt of a non-toxic organic acid or inorganic acid, such as a hydrochloride, odor Also included are hydrides, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acidic functional, non-toxic acceptable cation counterion. The cation is represented by sodium cation, potassium cation, calcium cation, magnesium cation, ammonium cation, tetraalkylammonium cation and the like.

  “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

  “Preventing” or “prevention” reduces the risk of developing a disease or disorder (ie, at least one of the clinical symptoms of the disease can be exposed to or is likely to become a disease, but is still a symptom of the disease Not to develop in a subject who has not experienced or may not have

  A “prodrug” has a cleavable group and becomes a compound of the invention that is pharmacologically active in vivo by solvolysis or under physiological conditions (including derivatives of the compounds of the invention) Say. Examples of such include, but are not limited to, choline ester derivatives and N-alkylmorpholine esters.

  A “solvate” usually refers to a form of a compound that is bound to a solvent by a solvolysis reaction. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared, for example, in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates.

  “Subject” includes humans. The terms “human”, “patient” and “subject” are used interchangeably herein.

  “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease, is sufficiently effective for the treatment of the disease. A “therapeutically effective amount” can vary depending on the compound, the disease and its severity, the age, weight, etc., of the subject to be treated.

  “Treating” or “treatment” of any disease or disorder, in one embodiment, ameliorates the disease or disorder (ie, stops or alleviates at least one of the disease progression or its clinical symptoms). Say. In another embodiment, “treating” or “treatment” refers to improving at least one physical parameter that may not be recognized by the subject. In yet another embodiment, “treating” or “treatment” refers to treating a disease or disorder physically (eg, recognizing a recognizable symptom), physiological (eg, stabilizing a physical parameter), Or it refers to adjusting in both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.

Other derivatives of the compounds of the present invention are active in both their acid and acidic derivative forms, but in acid, sensitive forms are often delayed in solubility, histocompatibility benefits, or in mammalian organs. Provides release (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, for example, esters prepared by reaction of the parent acid with an appropriate alcohol, prepared by reaction of the parent acid compound with a substituted or unsubstituted amine. Amines, acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amines, and anhydrides derived from acidic groups pendant on the compounds of the present invention are preferred prodrugs. It may be desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters. Preferred are C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, aryl, C ₇ -C ₁₂ substituted aryl and C ₇ -C ₁₂ arylalkyl esters of the compounds of the present invention.

As used herein, the term “isotope variant” refers to a compound that contains an unnatural proportion of isotopes at one or more of the atoms that constitute the compound. For example, an “isotopic variant” of a compound includes one or more non-radioactive isotopes such as deuterium ( ² H or D), carbon-13 ( ¹³ C), nitrogen-15 ( ¹⁵ N), and the like. sell. For compounds in which isotope substitution occurs, the following atoms, if present, are such that any hydrogen is ² H / D, any carbon is ¹³ C, and any nitrogen is ¹⁵ N: It will be appreciated that the presence and substitution of such atoms can be determined within the skill of the art. Similarly, the present invention may include the preparation of isotopic variants with radioisotopes, for example when the resulting compounds are used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful for this purpose due to their simple introduction and simple means of detection. In addition, compounds substituted with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, may be prepared, for example, by positron emission tomography to examine substrate receptor occupancy. Useful in (PET) studies.

  All isotope variants listed herein, whether radioactive or non-radioactive, are intended to be included within the scope of the present invention.

  It is also understood that compounds that have the same molecular formula but differ in nature, order of bonding of atoms, or arrangement of atoms in space are “isomers”. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers".

  Stereoisomers that are not mirror images of one another are called “diastereomers”, and stereoisomers that are non-superimposable mirror images of each other are called “enantiomers”. Where a compound has an asymmetric center, for example when four different groups are attached to it, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers, either according to the Cahn prelog R- and S-sequencing rules, or by molecules rotating the plane of polarized light and dextrorotatory or levorotatory (ie, ( +) Or (−)-isomers). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a “racemic mixture”.

  “Tautomers” are compounds that are interconvertible forms of a particular compound structure and that change by the transfer of hydrogen atoms and electrons. Thus, the two structures are in equilibrium due to the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with acids or bases. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, which are likewise formed by treatment with acids or bases.

  Tautomeric forms may be associated with achieving optimal chemical reactivity and biological activity of the compound of interest.

  The compounds of the present invention may have one or more asymmetric centers and are therefore prepared as individual (R)-or (S) -stereoisomers or as mixtures thereof. can do. Unless otherwise stated, the description and nomenclature of a particular compound herein and in the claims is intended to include both the individual enantiomers and mixtures, racemates or other mixtures thereof. Methods for stereochemistry determination and stereoisomer separation are well known in the art.

(Compound)
The present invention, in a mammal, related to abnormalities of the activity of a wide range of P2X ₇ receptor state, inter alia, rheumatoid arthritis, Parkinson's disease, uveitis, asthma, cardiovascular, such as myocardial infarction conditions, pain syndromes Treatment and prevention (acute and chronic or neuropathic), prevention and / or prevention of inflammatory bowel diseases and immune dysfunctions such as traumatic brain injury, acute spinal cord injury, neurodegenerative disorders, autoimmune disorders or autoimmune conditions Bicycloheteroaryl compounds useful for treatment are provided.

In a first aspect of the present invention, it is possible to modulate the activity in vivo P2X ₇ receptors, of formula (I):

（式中、
ＢおよびＹは、独立して、ＣＲ^２ａおよびＣＲ^２ａＲ^２ｂから選択され；
Ｗ、Ｗ’およびＺは、独立して、ＣＲ^４およびＮから選択されるが、ただし、Ｗ、Ｗ’およびＺの３つ全てが同時にＮであることはなく；
Ｌ^１は、置換または非置換のＣ_１−Ｃ_５アルキレンであり；
ｎは、０、１、２、３、または４であり；
Ｒ^１は、置換または非置換の３〜１３員シクロアルキル環、３〜１３員ヘテロシクロアルキル環、３〜１３員アリール環および３〜１３員ヘテロアリール環から選択され；
Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２’およびＲ^２’’の各々は、独立して、水素、ハロ、および置換または非置換のＣ_１−Ｃ_６アルキルから選択されるか；あるいはＲ^２’およびＲ^２’’のいずれかが一緒になって、３〜７個の原子のシクロアルキル環またはシクロヘテロアルキル環を形成し；
Ｒ^３は、水素またはアシル、置換アシル、置換または非置換のアシルアミノ、置換または非置換のアルキルアミノ、置換または非置換のジアルキルアミノ、置換または非置換のアルキルチオ、置換または非置換のアルコキシ、アルコキシカルボニル、置換アルコキシカルボニル、置換または非置換のアルキルアリールアミノ、アリールアルキルオキシ、置換アリールアルキルオキシ、アリール、置換アリール、アリールアルキル、置換または非置換のスルホキシド、置換または非置換のスルホン、置換または非置換のスルファニル、置換または非置換のアミノスルホニル、置換または非置換のアリールスルホニル、硫酸、硫酸エステル、置換または非置換のカルバモイル、シアノ、置換または非置換のシクロアルキル、置換または非置換のシクロヘテロアルキル、ハロ、ヘテロアリールオキシ、置換または非置換のヘテロアリール、置換または非置換のヘテロアルキル、ニトロおよびチオから選択される官能基であるが；ただしＲ^３は、水素結合供与基以外であり；
Ｒ^４は、独立して、Ｈ、アルキル、置換アルキル、アシル、置換アシル、置換または非置換のアシルアミノ、置換または非置換のアルキルアミノ、置換または非置換のアルキルチオ、置換または非置換のアルコキシ、アルコキシカルボニル、置換アルコキシカルボニル、置換または非置換のアルキルアリールアミノ、アリールアルキルオキシ、置換アリールアルキルオキシ、アミノ、アリール、置換アリール、アリールアルキル、置換または非置換のスルホキシド、置換または非置換のスルホン、置換または非置換のスルファニル、置換または非置換のアミノスルホニル、置換または非置換のアリールスルホニル、硫酸、硫酸エステル、置換または非置換のジヒドロキシホスホリル、置換または非置換のアミノジヒドロキシホスホリル、アジド、カルボキシ、置換または非置換のカルバモイル、シアノ、置換または非置換のシクロアルキル、置換または非置換のシクロヘテロアルキル、置換または非置換のジアルキルアミノ、ハロ、ヘテロアリールオキシ、置換または非置換のヘテロアリール、置換または非置換のヘテロアルキル、ヒドロキシ、ニトロおよびチオから選択され；
点線の結合は、単結合または二重結合である）
を有するビシクロヘテロアリール化合物、あるいはその医薬的に許容し得る塩、溶媒和物またはプロドラッグ、ならびにその立体異性体、同位体改変体および互変異性体が開示される。

(Where
B and Y are independently selected from CR ^2a and CR ^2a R ^2b ;
W, W ′ and Z are independently selected from CR ⁴ and N, provided that all three of W, W ′ and Z are not N at the same time;
L ¹ is a substituted or unsubstituted C ₁ -C ₅ alkylene;
n is 0, 1, 2, 3, or 4;
R ¹ is selected from a substituted or unsubstituted 3-13 membered cycloalkyl ring, 3-13 membered heterocycloalkyl ring, 3-13 membered aryl ring and 3-13 membered heteroaryl ring;
Each of R ^2a , R ^2b , R ^{2 ′} and R ^{2 ″} is independently selected from hydrogen, halo, and substituted or unsubstituted C ₁ -C ₆ alkyl; or R ^{2 ′} and R Any of ^{2 ″} together form a 3-7 atom cycloalkyl or cycloheteroalkyl ring;
R ³ is hydrogen or acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl , Substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted Sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfate ester, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted A functional group selected from chloroheteroalkyl, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, nitro and thio; provided that R ³ is other than a hydrogen bond donating group Yes;
R ⁴ is independently H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxy Carbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or Unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfate ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, Carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted hetero Selected from aryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro and thio;
(The dotted bond is a single bond or a double bond)
Disclosed are bicycloheteroaryl compounds having the formula: or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, isotopic variants and tautomers thereof.

  In a further embodiment, with respect to compounds of formula I, n is 0-4. In another embodiment, n is 0-2. In certain embodiments, n is 1.

In a further embodiment, with respect to compounds of formula I, L ¹ is C ₁ -C ₅ which is unsubstituted or substituted with one or more substituents selected from alkyl, oxo, aryl, hydroxyl or hydroxyalkyl. An alkylene group;

In a further embodiment, with respect to compounds of formula I, B and Y are independently selected from CR ^2a and CR ^2a R ^2b .

In a further embodiment, with respect to compounds of formula I, B and Y are independently selected from CR ^2a R ^2b and the dotted bond is a single bond.

In a further embodiment, with respect to compounds of formula I, B and Y all represent CH ₂ and the dotted bond is a single bond.

In a further embodiment, with respect to compounds of formula I, B and Y are independently selected from CR ^2a and the dotted bond is a double bond.

  In a further embodiment, with respect to compounds of formula I, B and Y all represent CH and the dotted bond is a double bond.

  In a further embodiment, with respect to compounds of formula I, n is 0, 1 or 2. In one particular embodiment, n is 1.

  In another embodiment, with respect to compounds of formula I:

基のＲ^２’およびＲ^２’’の各々は、ＨまたはＭｅである。特定の一実施形態では、Ｒ^２’およびＲ^２’’の各々は、Ｈである。

Each of the radicals R ^{2 ′} and R ^{2 ″} is H or Me. In one particular embodiment, each of R ^{2 ′} and R ^{2 ″} is H.

  In a further embodiment, with respect to compounds of formula I:

基のＲ^２’およびＲ^２’’の１つは、Ｍｅ、Ｅｔ、ハロおよびＣｌから選択されてよく、もう１つは、Ｈである。

One of the radicals R ^{2 ′} and R ^{2 ″} may be selected from Me, Et, halo and Cl, and the other is H.

In a further embodiment, with respect to compounds of formula I, R ¹ is substituted or unsubstituted aryl. In one particular embodiment, R ¹ is substituted or unsubstituted phenyl.

In a further embodiment, with respect to compounds of formula I, R ¹ is a substituted or unsubstituted cycloalkyl. In another embodiment, R ¹ is substituted or unsubstituted adamantyl. In yet another embodiment, R ¹ is substituted or unsubstituted cyclohexyl or cycloheptyl.

  In a further embodiment, with respect to compounds of formula I, each of W and W 'is N.

In a further embodiment, with respect to compounds of formula I, each of W, Z, and W ′ is CR ⁴ . In one particular embodiment, each of W, Z and W ′ is CH.

In a further embodiment, with respect to compounds of formula I, each of W and Z is CR ⁴ , W ′ is CR ⁵ and R ⁵ is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl and halo Is done. In one particular embodiment, R ⁵ is selected from Me, cyclopropyl, Cl, F and CF ₃ .

  In another embodiment, with respect to compounds of formula I, the compounds are of formula II, III or IV:

（式中、
ＷはＣＲ^４であり；ＺはＣＲ^４であり；
Ｌ^１、Ｒ^１、Ｒ^２’、Ｒ^２’’、Ｒ^３およびＲ^４は、式Ｉの通りであり；
Ｒ^５は、Ｈ、アルキル、置換アルキル、アシル、置換アシル、置換または非置換のアシルアミノ、置換または非置換のアルキルアミノ、置換または非置換のアルキルチオ、置換または非置換のアルコキシ、アルコキシカルボニル、置換アルコキシカルボニル、置換または非置換のアルキルアリールアミノ、アリールアルキルオキシ、置換アリールアルキルオキシ、アミノ、アリール、置換アリール、アリールアルキル、置換または非置換のスルホキシド、置換または非置換のスルホン、置換または非置換のスルファニル、置換または非置換のアミノスルホニル、置換または非置換のアリールスルホニル、硫酸、硫酸エステル、置換または非置換のジヒドロキシホスホリル、置換または非置換のアミノジヒドロキシホスホリル、アジド、カルボキシ、置換または非置換のカルバモイル、シアノ、置換または非置換のシクロアルキル、置換または非置換のシクロヘテロアルキル、置換または非置換のジアルキルアミノ、ハロ、ヘテロアリールオキシ、置換または非置換のヘテロアリール、置換または非置換のヘテロアルキル、ヒドロキシ、ニトロおよびチオから選択される）
で表されるか、あるいはその医薬的に許容し得る塩、溶媒和物またはプロドラッグ、ならびにその立体異性体、同位体改変体および互変異性体である。

(Where
W is CR ⁴ ; Z is CR ⁴ ;
L ¹ , R ¹ , R ^{2 ′} , R ^{2 ″} , R ³ and R ⁴ are as in Formula I;
R ⁵ is H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxy Carbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl Substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfate ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, azide, carbo Xyl, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, Selected from substituted or unsubstituted heteroalkyl, hydroxy, nitro and thio)
Or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, isotopic variants and tautomers thereof.

In another embodiment, with respect to compounds of formulas III-IV, R ^{2 ′} and R ^{2 ″} are each H.

In another embodiment, with respect to compounds of formulas III-IV, R ^{2 ′} is halo; R ^{2 ″} is H.

In another embodiment, with respect to compounds of formulas III-IV, R ^{2 ′} is Cl or F; R ^{2 ″} is H.

In another embodiment, with respect to compounds of formulas III - IV, R ^{2 'is} an Me or Et; R ^2''is H.

In another embodiment, with respect to compounds of formulas III-IV, R ^{2 ′} and R ^{2 ″} are each Me.

In a more particular embodiment, with respect to compounds of formulas III-IV, R ^{2 ′} is Me; R ^{2 ″} is H.

In another embodiment, with respect to compounds of formulas II-IV, R ¹ is a substituted or unsubstituted aryl.

In another embodiment, with respect to compounds of formulas II-IV, R ¹ is a substituted or unsubstituted phenyl or naphthalene.

In another embodiment, with respect to compounds of formulas II-IV, R ¹ is a substituted or unsubstituted naphthalene.

In another embodiment, with respect to compounds of formulas II-IV, ^{R 1} is an unsubstituted naphthalene.

In another embodiment, with respect to compounds of formulas II-IV, R ¹ is a substituted or unsubstituted phenyl.

In another embodiment, with respect to compounds of formulas II-IV, R ¹ is a substituted or unsubstituted heteroaryl.

In another embodiment, with respect to compounds of formulas II-IV, each R ¹ is substituted or unsubstituted pyridyl, substituted or unsubstituted quinoline, substituted or unsubstituted benzodioxole, substituted or unsubstituted benzo Dioxane, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiophene, or substituted or unsubstituted benzodioxepin.

  In another embodiment, with respect to compounds of formula I, formula V, VI or VII:

（式中、
ＷはＣＲ^４であり；Ｚは、ＣＲ^４であり；
Ｌ^１、Ｒ^１、Ｒ^２’、Ｒ^２’’、Ｒ^３およびＲ^４は、式Ｉに記載された通りであり；Ｒ^５は、式ＩＩ〜ＩＶに記載された通りであり；
Ｒ^４ａは、Ｈ、アルキル、置換アルキル、アシル、置換アシル、置換または非置換のアシルアミノ、置換または非置換のアルキルアミノ、置換または非置換のアルキルチオ、置換または非置換のアルコキシ、アリールオキシ、アルコキシカルボニル、置換アルコキシカルボニル、置換または非置換のアルキルアリールアミノ、アリールアルキルオキシ、置換アリールアルキルオキシ、アミノ、アリール、置換アリール、アリールアルキル、置換または非置換のスルホキシド、置換または非置換のスルホン、置換または非置換のスルファニル、置換または非置換のアミノスルホニル、置換または非置換のアリールスルホニル、硫酸、硫酸エステル、置換または非置換のジヒドロキシホスホリル、置換または非置換のアミノジヒドロキシホスホリル、アジド、カルボキシ、置換または非置換のカルバモイル、シアノ、置換または非置換のシクロアルキル、置換または非置換のシクロヘテロアルキル、置換または非置換のジアルキルアミノ、ハロ、ヘテロアリールオキシ、置換または非置換のヘテロアリール、置換または非置換のヘテロアルキル、ヒドロキシ、ニトロおよびチオから選択され；ｍは、０〜５から選択される）
で表されるか、またはその溶媒和物もしくはプロドラッグ；ならびにその立体異性体、同位体改変体および互変異性体である。

(Where
W is CR ⁴ ; Z is CR ⁴ ;
L ¹ , R ¹ , R ^{2 ′} , R ^{2 ″} , R ³ and R ⁴ are as described in Formula I; R ⁵ is as described in Formulas II-IV;
R ^4a is H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl , Substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted Substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfate ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl Ru, azide, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted Of heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro and thio; m is selected from 0 to 5)
Or a solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof.

  With respect to the compounds of the invention as described hereinbefore and wherever m is 0-5, it should be understood that when m = 0, the ring is unsubstituted. .

In one embodiment, with respect to compounds of formulas VI-VII, R ^{2 ′} and R ^{2 ″} are each H.

In another embodiment, with respect to compounds of formulas VI-VII, R ^{2 ′} is halo and R ^{2 ″} is H.

In another embodiment, with respect to compounds of formulas VI-VII, R ^{2 ′} is Cl or F; R ^{2 ″} is H.

In another embodiment, with respect to compounds of formula VI~VII, R ^{2 'is} an Me or Et; R ^2''is H.

In another embodiment, with respect to compounds of formulas VI-VII, R ^{2 ′} and R ^{2 ″} are each Me.

In a more particular embodiment, with respect to compounds of formulas VI-VII, R ^{2 ′} is Me; R ^{2 ″} is H.

  In another embodiment, with respect to compounds of formula I, the compounds are of formula VIII, IX or X:

（式中、
ＷはＣＲ^４であり；ＺはＣＲ^４であり；
Ｌ^１、Ｒ^３およびＲ^４は、式Ｉで記載した通りであり；Ｒ^５は、式ＩＩ〜ＩＶで記載した通りであり；ｍおよびＲ^４ａは、式Ｖ〜ＶＩＩで記載した通りであり；Ｒ^２’は、ＨまたはＭｅであり；Ｃｙは、アダマンチル、シクロヘキシルまたはシクロヘプチルであり；各Ｒ^４ｂは、独立して、Ｃ_１−Ｃ_４アルキルおよびヒドロキシから選択される）
で表されるか、あるいはその医薬的に許容し得る塩、溶媒和物またはプロドラッグ、ならびにその立体異性体、同位体改変体および互変異性体である。

(Where
W is CR ⁴ ; Z is CR ⁴ ;
L ¹ , R ³ and R ⁴ are as described in formula I; R ⁵ is as described in formulas II-IV; m and R ^4a are as described in formulas V-VII. R ^{2 ′} is H or Me; Cy is adamantyl, cyclohexyl or cycloheptyl; each R ^4b is independently selected from C ₁ -C ₄ alkyl and hydroxy;
Or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers, isotopic variants and tautomers thereof.

In one embodiment, with respect to compounds of formulas V-X, R ^{2 ′} is H or Me. In another embodiment, R ² ′ is Me. In one particular embodiment, R ^{2 ′} is H.

  In another embodiment, with respect to compounds of formulas V-X, m is 1, 2 or 3.

  In another embodiment, with respect to compounds of formulas V-X, m is 1 or 2. In certain embodiments, m is 1.

In another embodiment, with respect to compounds of formulas V-X, each R ^4a is independently Me _, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF ₃ , _{CHF 2, OCF 3, i-} Pr, i-Bu, t-Bu, SMe, CH = CH-CO 2 H, SOMe, SO 2 Me, SO 3 H, is selected from _SO 3 Me and pyridyl.

In another embodiment, with respect to compounds of formulas I through X, ^{L 1} _is a C 1 -C ₅ alkylene group.

In another embodiment, with respect to compounds of formulas I-X, L ¹ is C ₁ —, which is unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, oxo and hydroxyalkyl. C ₅ alkylene group.

In another embodiment, with respect to compounds of formulas I-X, L ¹ is unsubstituted or substituted with one or more substituents selected from Me, Et, i-Pr, hydroxy and hydroxymethyl. It is an ethylene group.

In another embodiment, with respect to compounds of formulas I-X, L ¹ is unsubstituted or substituted with one or more substituents selected from Me, Et, i-Pr and hydroxymethyl It is a group.

In another embodiment, with respect to compounds of formulas I-X, R ³ is selected from alkyl, dialkylamino, acyloxy, alkoxy, and —SO ₂ -alkyl.

In another embodiment, with respect to compounds of formulas I through X, ^{R 3} _{is, t-Bu, NMe2, SO} 2 Me, selected from OMe and OCOMe.

In another embodiment, with respect to compounds of formulas I through X, R ³ is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl or cycloheteroalkyl.

In another embodiment, with respect to compounds of formulas I through X, R ³ is a substituted or unsubstituted phenyl, pyridyl, pyran, tetrahydropyran, piperidine, morpholine, pyrrolidine, pyrrolidinone and benzodioxane.

In another embodiment, with respect to compounds of formulas I-X, the group: -L ₁ -R ³ is

から選択される。

Selected from.

  In another embodiment, with respect to compounds of formula I, the compounds are of formula XIa, XIb, XIc, XId, XIe, XIf, XIg, XIh or XIj:

（式中、ｍおよびＲ^４ａは、式Ｖ〜ＶＩＩに記載された通りであり；Ｒ^５は、Ｈ、アルキルまたはハロから選択される）
で表される。

Wherein m and R ^4a are as described in formulas V-VII; R ⁵ is selected from H, alkyl or halo
It is represented by

  In one embodiment, with respect to compounds of formulas V-XIj, m is 1, 2 or 3.

  In another embodiment, with respect to compounds of formulas V-XIj, m is 1 or 2. In certain embodiments, m is 2.

In another embodiment, with respect to compounds of formulas V-XIj, each R ^4a is independently Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF ₃ , _{CHF 2, OCF 3, i-} Pr, i-Bu, t-Bu, SMe, CH = CH-CO 2 H, SOMe, SO 2 Me, SO 3 H, is selected from _SO 3 Me and pyridyl.

In another embodiment, with respect to compounds of formulas V-XIj, m is 1 and R ^4a is CF ₃ .

In another embodiment, with respect to compounds of formulas V-XIj, m is 2 and R ^4a is F and CF ₃ .

In another embodiment, with respect to compounds of formulas V-XIj, m is 2 and R ^4a is F and Cl.

  In another embodiment, with respect to compounds of formula I, the compounds are of formula XIIa, XIIb, XIIc, XIId, XIIe, XIIf, XIIg, XIIh or XIIj:

（式中、Ｃｙは、シクロヘキシルまたはシクロヘプチルであり；Ｒ^４ａは、独立して、水素、アルキル、置換アルキルまたはヒドロキシルから選択され；ｍは、０〜５から選択され；Ｒ^５は、Ｈ、アルキルまたはハロから選択される）
で表される。

Wherein Cy is cyclohexyl or cycloheptyl; R ^4a is independently selected from hydrogen, alkyl, substituted alkyl or hydroxyl; m is selected from 0 to ⁵ ; R ⁵ is H, Selected from alkyl or halo)
It is represented by

In another embodiment, with respect to compounds of formulas XIIa-XIIj, Cy is cyclohexyl; m is 1 and R ^4a is hydroxy.

In another embodiment, with respect to compounds of formulas XIIa-XIIj, m is 1 and R ^4a is hydroxy.

In another embodiment, with respect to compounds of formulas XIIa-XIIj, m is 1-4 and R ^4a is methyl.

In another embodiment, with respect to compounds of formulas XIIa-XIIj, m is 1-4 and R ^4a is methyl.

In one embodiment, each of the relates to compounds of formula I through X, W and Z are independently CR ^4.

  In one embodiment, with respect to compounds of formulas I-X, each of W and Z is independently CH.

  In one embodiment, for the compounds of formulas I-X, W is N.

  In one embodiment, with respect to compounds of formulas I-X, W is N and Z is H.

In one embodiment, with respect to compounds of formulas II-XIIj, R ⁵ is H.

In one embodiment, with respect to compounds of formulas II-XXIIj, R ⁵ is selected from alkyl, cycloalkyl, substituted alkyl, and halo. In one particular embodiment, R ⁵ is selected from Me, cyclopropyl, Cl, F and CF ₃ .

In one embodiment, with respect to compounds of formulas II-XIIj, R ⁵ is Me.

In one embodiment, with respect to compounds of formulas II-XIIj, R ⁵ is CF ₃ .

In one embodiment, with respect to compounds of formulas II-XIIj, R ⁵ is F.

In a further embodiment, with respect to compounds of formulas II-XIIj, R ⁵ is Cl.

In a further embodiment relates to compounds of Formula II~XIIId, ^{R 5} is cyclopropyl.

  In certain embodiments, prodrugs and derivatives of the compounds described in the formulas above are provided. Prodrugs and derivatives of the present invention are compounds that have metabolically degradable groups and become pharmacologically active compounds of the present invention in vivo by solvolysis or under physiological conditions. Examples of these include, but are not limited to, choline ester derivatives and the like, and N-alkylmorpholine esters.

Other derivatives of the compounds of the invention are active in both their acid and acidic derivative forms, but acid-sensitive forms are often delayed in solubility, histocompatibility benefits, or in mammalian organs. Provides release (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, for example, esters prepared by reaction of the parent acid with an appropriate alcohol, prepared by reaction of the parent acid compound with a substituted or unsubstituted amine. Amines, acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amines, and anhydrides derived from acidic groups hanging on the compounds of the present invention are preferred prodrugs. It may be desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters. Preferred are C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, aryl, C ₇ -C ₁₂ substituted aryl and C ₇ -C ₁₂ arylalkyl esters of the compounds of the present invention.

(Pharmaceutical composition)
When used as a medicament, the compounds of the present invention are usually administered in the form of a pharmaceutical composition. Such compositions can be prepared by methods well known in the pharmaceutical industry and comprise at least one active compound.

  Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of compound actually administered usually includes the condition to be treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. Determined by experts, taking into account relevant circumstances.

  The pharmaceutical compositions of the present invention are administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Depending on the intended route of delivery, the compounds of the invention are preferably formulated as injectable or oral compositions or as ointments, lotions or patches for transdermal administration.

  Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. More generally, however, the composition is present in unit dosage form to facilitate accurate dosing. The term “unit dosage form” refers to a physically discrete unit suitable for unit dosage for human subjects and other mammals, each unit with a suitable pharmaceutical excipient to achieve the desired therapeutic effect. Contains a predetermined amount of active substance calculated to exert. Exemplary unit dosage forms include prefilled ampoules or syringes filled with liquid compositions, pills, tablets, capsules and the like in the case of solid compositions. In such compositions, the furan sulfonic acid compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or A carrier and processing aids that help to form the desired dosage form.

  Liquid forms suitable for oral administration include suitable aqueous or non-aqueous vehicles, and buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds having similar properties: binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose, Disintegrating agents such as alginic acid, primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; Alternatively, fragrances such as peppermint, methyl salicylate or orange fragrances.

  Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As mentioned above, the active compound of the composition is usually a minor component, about 0.05 to 10% by weight, the remainder being an injectable carrier or the like.

  The transdermal composition usually contains the active ingredient generally in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, More preferably, it is formulated as a topical ointment or cream containing about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is usually combined with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with, for example, an oil-in-water cream base. Such transdermal preparations are well known in the art and generally comprise additional ingredients that enhance the stable skin penetration of the active ingredient or preparation. All such known transdermal preparations and ingredients are included within the scope of the present invention.

  The compounds of the present invention can also be administered by a transdermal device. Thus, transdermal administration can be accomplished using either a reservoir or porous membrane type patch, or a solid matrix variant patch.

  The components described above as compositions for oral administration, injection or topical administration are merely representative. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences Part 8, 17th Edition, 1985, Mack Publishing, Easton, Pennsylvania, which is incorporated herein by reference.

  The compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

  The following formulation examples illustrate representative pharmaceutical compositions of the present invention. However, the present invention is not limited to the following pharmaceutical composition.

(Prescription 1-Tablet)
The compound of the invention is mixed as a dry powder with a dry gelatin binder in an approximate 1: 2 weight ratio. Add a small amount of magnesium stearate as a lubricant. The mixture is made into 240-270 mg tablets (80-90 mg of active amide compound per tablet) using a tablet press.

(Prescription 2-Capsule)
The compound of the present invention is mixed as a dry powder with a starch diluent in an approximate 1: 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active amide compound per capsule).

(Formulation 3-solution)
The compound of the present invention (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) were mixed and 10 mesh U.S. S. Pass through sieve and then mix with pre-made aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavor and pigment are diluted with water and added with stirring. Sufficient water is then added to bring the total volume to 5 mL.

(Prescription 4-tablets)
The compound of the invention is mixed as a dry powder with a dry gelatin binder in an approximate 1: 2 weight ratio. Add a small amount of magnesium stearate as a lubricant. Using a tableting machine, the mixture is made into 450-900 mg tablets (150-300 mg of active amide compound).

(Formulation 5-Injection)
The compound of the present invention is dissolved or suspended in a sterile buffered saline aqueous medium for injection to a concentration of about 5 mg / ml.

(Prescription 6-topical use)
Stearyl alcohol (250 g) and white petrolatum (250 g) are melted at about 75 ° C., then the compound of the invention (50 g), methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g) and A mixture of propylene glycol (120 g) dissolved in water (about 370 g) is added and stirred until the resulting mixture solidifies.

(Treatment method)
The compounds of the present invention, in a mammal, are used as therapeutic agents for the treatment of conditions in which aberrant activity of P2X ₇ receptors are or caused by causally related. Accordingly, the compounds and pharmaceutical compositions of the present invention find use as therapeutic agents for preventing and / or treating autoimmune, inflammatory and cardiovascular conditions in mammals, including humans.

  In a method of treatment, the present invention is susceptible to or suffering from conditions associated with arthritis, uveitis, asthma, myocardial infarction, traumatic brain injury, acute spinal cord injury, inflammatory bowel disease and autoimmune disorders A method for treating a mammal is provided, wherein an effective amount of one or more of the pharmaceutical compositions described above is administered.

  In yet another treatment method aspect, the present invention is for treating a mammal susceptible to or suffering from a condition that causes a pain response or is associated with an imbalance in maintenance of sensory nerve basal activity. Provide a method. The amines of the present invention can be of various origins or causes, such as acute, inflammatory pain (eg, pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (eg, zonal) Induced by postherpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillain-Barre syndrome, fibromyalgia, phantom limb pain, postmastectomy pain, peripheral neuropathy, HIV neuropathy and chemotherapy Visceral pain (eg, gastroesophageal reflux disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gynecological and urological disorders) ), Use as an analgesic for the treatment of toothache and headache (eg, migraine, cluster headache and tension headache).

  In a further method of treatment aspect, the invention relates to neurodegenerative diseases and disorders, such as Parkinson's disease, multiple sclerosis; diseases and disorders mediated by or resulting in neuroinflammation, such as traumatic brain injury. And encephalitis; neuropsychiatric diseases and disorders through the center, such as manic depression, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognitive disorders; epilepsy and seizure disorders; prostate dysfunction Bladder and bowel dysfunction such as urinary incontinence, dysuria, rectal hypersensitivity, fecal incontinence, benign prostatic hyperplasia and inflammatory bowel disease; respiratory and respiratory tract diseases and disorders such as allergic rhinitis, asthma And reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders mediated by or resulting in inflammation, eg, rheumatoid arthritis Osteoarthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders, uveitis and atherosclerosis; itch / itch, eg, psoriasis; obesity; lipid disorders; cancer; blood pressure; spinal cord injury; As well as a method of treating a mammal susceptible to or suffering from renal dysfunction, said method comprising one of an amount effective to treat or prevent the condition There is provided a method comprising administering the above pharmaceutical composition.

  In a further aspect of the invention there is provided the use of a compound of the invention as a formulation, particularly in the treatment or prevention of the conditions and diseases described above. The present invention also provides the use of a compound herein in the preparation of a medicament for the treatment or prevention of one of the above conditions and diseases.

  Injection dose concentrations range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all administered for about 1 to about 120 hours, especially 24 to 96 hours. From about 0.1 mg / kg to about 10 mg / kg or more of a pre-bolus may be administered to achieve the proper steady state concentration. The maximum total dose is not expected to exceed about 2 g / day for a 40-80 kg human patient.

  For prevention and / or treatment of long-term conditions such as neurodegenerative conditions and autoimmune conditions, treatment regimens usually extend over months or years, so oral administration is patient convenience and tolerability Is preferred. For oral dosing, a typical regimen is 1 to 5 times per day, especially 2 to 4 times, usually 3 times daily. Using these dosing patterns, each dose is given from about 0.01 to about 20 mg / kg of a compound of the invention, preferably each dose is from about 0.1 to about 10 mg / kg, especially about 1 to about 5 mg / kg is given.

  The transdermal dose is generally selected to provide a concentration that is the same or lower than the blood concentration achieved using the injected dose.

  When used to prevent the development of a neurodegenerative, autoimmune or inflammatory condition, the compounds of the invention are at the risk of developing the condition at the dose concentration, under the advice and supervision of a physician. Administer to a patient. Patients at risk for developing a particular condition generally include a family member of the condition or a person who has been identified as being particularly suspected of developing the condition by genetic testing or genetic screening.

  The compounds of the present invention can be administered as a single active agent or include other compounds that exhibit the same or similar therapeutic activity and have been found to be safe and effective in combination administration It can also be administered in combination with other drugs.

(General synthesis procedure)
The bicycloheteroaryl compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It is understood that if there are typical or preferred process conditions (ie reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions can be used unless otherwise stated. Will be done. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

  Furthermore, as will be appreciated by those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Selection of appropriate protecting groups for a particular functional group, and appropriate conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, their introduction and removal, are described in T.W. W. Greene and P.M. G. M.M. Wuts, Protecting Groups in Organic Synthesis, 2nd edition, Wiley, New York, 1991 and references cited therein.

  The preparation of representative bicycloheteroaryls listed herein above is described in detail in the following scheme. The compounds of the invention are prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

  Representative scheme 1

代表的スキーム２

Representative scheme 2

式中、Ｒ’＝Ｒ^１、およびＲ＝−Ｌ^１−Ｒ^３である
中間体の合成
中間体１
２−（２−（ジメチルアミノ）−ビニル）−３−ニトロ安息香酸（Ｅ）−メチルの調製：

Wherein R ′ = R ¹ and R = —L ¹ —R ³ Synthesis of Intermediate Intermediate 1
Preparation of 2- (2- (dimethylamino) -vinyl) -3-nitrobenzoic acid (E) -methyl:

２−メチル−３−ニトロ安息香酸メチル（５．０ｇ、２５．６ｍｍｏｌ）およびＮ，Ｎ−ジメチルホルムアミドジメチルアセタール（９．１８ｇ、７７ｍｍｏｌ）の混合物を、ＤＭＦ（３０ｍＬ）中、１１５℃で１７時間攪拌した。揮発物質を減圧除去し、２−（２−（ジメチルアミノ）−ビニル）−３−ニトロ安息香酸（Ｅ）−メチルを褐色油状物として得た。

A mixture of methyl 2-methyl-3-nitrobenzoate (5.0 g, 25.6 mmol) and N, N-dimethylformamide dimethyl acetal (9.18 g, 77 mmol) in DMF (30 mL) at 115 ° C. for 17 hours. Stir. Volatiles were removed under reduced pressure to give 2- (2- (dimethylamino) -vinyl) -3-nitrobenzoic acid (E) -methyl as a brown oil.

中間体２
５−ニトロ−１Ｈ−イソクロメン−１−オンの調製：

Intermediate 2
Preparation of 5-nitro-1H-isochromen-1-one:

２−（２−（ジメチルアミノ）ビニル）−３−ニトロ安息香酸（Ｅ）−メチルを、ＥｔＯＡｃ（２００ｍＬ）に再溶解し、シリカゲル（２００ｇ）を加えた。得られた懸濁液を室温で１時間攪拌した。ＥｔＯＡｃ溶液をろ取した。シリカゲルをＥｔＯＡｃ（２×１５０ｍＬ）で洗浄し、合わせた有機物を蒸発し、減圧下で乾燥し、５−ニトロ−１Ｈ−イソクロメン−１−オン（４．０ｇ、２１．０ｍｍｏｌ、２工程後８２％）を褐色固体として得た。

2- (2- (Dimethylamino) vinyl) -3-nitrobenzoic acid (E) -methyl was redissolved in EtOAc (200 mL) and silica gel (200 g) was added. The resulting suspension was stirred at room temperature for 1 hour. The EtOAc solution was collected by filtration. The silica gel was washed with EtOAc (2 × 150 mL), the combined organics were evaporated, dried under reduced pressure, and 5-nitro-1H-isochromen-1-one (4.0 g, 21.0 mmol, 82% after 2 steps) ) Was obtained as a brown solid.

ＨＰＬＣ保持時間：１．７２分、１０〜１００％ＣＨ_３ＣＮ、３．５分勾配；ＥＳＩ−ＭＳｍ／ｚ１９２．１（Ｍ＋Ｈ）^＋。

HPLC retention time: 1.72 min, _10~100% CH 3 CN, 3.5 min gradient; ESI-MSm / z192.1 (M + H) +.

  For more information see McDonald, M .; C. Et al., British J. et al. Pharmacol. 2000, 130, 843, which is incorporated herein by reference.

Intermediate 3
Preparation of 5-amino-1H-isochromen-1-one

塩化スズ（ＩＩ）二水和物（４１．９ｇ、１８５．７ｍｍｏｌ）を、攪拌した５−ニトロ−１Ｈ−イソクロメン−１−オン（７．１ｇ、３７．１ｍｍｏｌ）の無水ＴＨＦ（１２０ｍＬ）溶液に加えた。反応混合物を室温で１８時間攪拌した。得られた混合物を、ＥｔＯＡｃ（４００ｍＬ）で希釈し、飽和重炭酸ナトリウム水溶液で処理し、ｐＨ＝１０とした。水（１００ｍＬ）を加え、層を分離した。水層を酢酸エチル（２×１５０ｍＬ）で抽出し、合わせた有機画分をＮａ_２ＳＯ_４で乾燥し、ろ過し、蒸発し、５−アミノ−１Ｈ−イソクロメン−１−オン（５．８ｇ、３６．０ｍｍｏｌ、９７％）を黄色固体として得た。

Tin (II) chloride dihydrate (41.9 g, 185.7 mmol) was added to a stirred solution of 5-nitro-1H-isochromen-1-one (7.1 g, 37.1 mmol) in anhydrous THF (120 mL). added. The reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was diluted with EtOAc (400 mL) and treated with saturated aqueous sodium bicarbonate solution to pH = 10. Water (100 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 150 mL) and the combined organic fractions were dried over Na ₂ SO ₄ , filtered and evaporated to 5-amino-1H-isochromen-1-one (5.8 g, 36.0 mmol, 97%) was obtained as a yellow solid.

ＨＰＬＣ保持時間：１．１６分、１０〜１００％ＣＨ_３ＣＮ、３．５分勾配；ＥＳＩ−ＭＳ ｍ／ｚ１６２．３（Ｍ＋Ｈ）^＋。さらなる情報は、Ｌｅｅ、Ｂ．Ｓ．ら、Ｊ．Ｏｒｇ．Ｃｈｅｍ．２００４、６９、３３１９に見出すことができ、これは参照により本明細書に援用される。

HPLC retention time: 1.16 min, _10~100% CH 3 CN, 3.5 min gradient; ESI-MS m / z162.3 ( M + H) +. For further information see Lee, B. et al. S. Et al. Org. Chem. 2004, 69, 3319, which is incorporated herein by reference.

Intermediate 4
Preparation of 2- (2-dimethylamino-ethyl) -5-nitro-2H-isoquinolin-1-one

５−ニトロ−イソクロメン−１−オン（１．０ｇ、５．２ｍｍｏｌ）およびＮ，Ｎ−ジメチル−１，２−エタンジアミン（４ｇ、４０ｍｍｏｌ）をメタノール（４０ｍＬ）中で１．５時間還流した。揮発物質をロータリーエバポレーターで除去し、残渣をフラッシュクロマトグラフィー（１２のシリカゲル、０〜７０％ＥｔＯＡｃ／ＣＨ_２Ｃｌ_２勾配）で精製し、２−（２−ジメチルアミノ−エチル）−５−ニトロ−２Ｈ−イソキノリン−１−オンを黄色固体（１．４ｇ、２．４ｍｍｏｌ、４６％）として得た。ＬＣ／ＭＳ（０．１％ギ酸変性剤）計算値（Ｍ＋１）^＋２６１．２８、測定値２６２．２。

5-Nitro-isochromen-1-one (1.0 g, 5.2 mmol) and N, N-dimethyl-1,2-ethanediamine (4 g, 40 mmol) were refluxed in methanol (40 mL) for 1.5 hours. Volatiles were removed on a rotary evaporator and the residue was purified by flash chromatography (12 silica gel, 0-70% EtOAc / CH ₂ Cl ₂ gradient) to give 2- (2-dimethylamino-ethyl) -5-nitro- 2H-isoquinolin-1-one was obtained as a yellow solid (1.4 g, 2.4 mmol, 46%). LC / MS (0.1% formic acid modifier) calculated (M + 1) ⁺ 261.28, measured 262.2.

中間体５
５−アミノ−２−（２−ジメチルアミノ−エチル）−２Ｈ−イソキノリン−１−オンの調製

Intermediate 5
Preparation of 5-amino-2- (2-dimethylamino-ethyl) -2H-isoquinolin-1-one

２−（２−ジメチルアミノ−エチル）−５−ニトロ−２Ｈ−イソキノリン−１−オン（０．６７ｇ、２．６ｍｍｏｌ）および脱水二塩化スズ（２ｇ、１０ｍｍｌ）をＴＨＦ（１０ｍＬ）中、室温で２４時間攪拌した。揮発物質をロータリーエバポレーターで除去し、残渣をＣＨ_２Ｃｌ_２（１Ｌ）に溶解し、飽和ＮａＨＣＯ_３水溶液（３０ｍＬ×３）で洗浄した。有機層をＮａ_２ＳＯ_４で乾燥し、ろ過し、濃縮乾固し、５−アミノ−２−（２−ジメチルアミノ−エチル）−２Ｈ−イソキノリン−１−オンを黄色固体として得た。化合物を、さらに精製することなく、次の工程で使用した。

2- (2-Dimethylamino-ethyl) -5-nitro-2H-isoquinolin-1-one (0.67 g, 2.6 mmol) and dehydrated tin dichloride (2 g, 10 ml) in THF (10 mL) at room temperature. Stir for 24 hours. Volatiles were removed on a rotary evaporator and the residue was dissolved in CH ₂ Cl ₂ (1 L) and washed with saturated aqueous NaHCO ₃ (30 mL × 3). The organic layer was dried over _Na 2 SO _4, filtered, concentrated to dryness, 5-amino-2 - (2-dimethylaminoethyl) -2H- isoquinolin-1-one as a yellow solid. The compound was used in the next step without further purification.

中間体６
２−アダマンタン−１−イル−Ｎ−（１−オキソ−１Ｈ−イソクロメン−５−イル）−アセトアミドの調製：

Intermediate 6
Preparation of 2-adamantan-1-yl-N- (1-oxo-1H-isochromen-5-yl) -acetamide:

５−アミノ−１Ｈ−イソクロメン−１−オン（２．９５ｇ、１８．３ｍｍｏｌ）およびＮＭＭ（２．０２ｍＬ、１８．３ｍｍｏｌ）の１，４−ジオキサン（５５ｍＬ）溶液に、１−メチルフェネチル酸クロライド（１８．３ｍｍｏｌ）の１，４−ジオキサン（４０ｍＬ）溶液を室温で滴下する。反応混合物を室温で３時間攪拌し、次いで、ＤＣＭ（４００ｍＬ）と水（２００ｍＬ）との間で分配する。層を分離する。水層をＤＣＭ（１００ｍＬ）で洗浄する。合わせた有機層を、硫酸ナトリウムで乾燥し、ろ過し、蒸発し、粗Ｎ−（１−オキソ−１Ｈ−イソクロメン−５−イル）−アセトアミド誘導体を得る。

To a solution of 5-amino-1H-isochromen-1-one (2.95 g, 18.3 mmol) and NMM (2.02 mL, 18.3 mmol) in 1,4-dioxane (55 mL) was added 1-methylphenethyl acid chloride ( A solution of 18.3 mmol) in 1,4-dioxane (40 mL) is added dropwise at room temperature. The reaction mixture is stirred at room temperature for 3 hours and then partitioned between DCM (400 mL) and water (200 mL). Separate the layers. Wash the aqueous layer with DCM (100 mL). The combined organic layers are dried over sodium sulfate, filtered and evaporated to give the crude N- (1-oxo-1H-isochromen-5-yl) -acetamide derivative.

  Preparation of N- [2- (2-dimethylamino-ethyl) -1-oxo-1,2-dihydro-isoquinolin-5-yl] -3-p-tolyl-propionamide):

５−アミノ−２−（２−ジメチルアミノ−エチル）−２Ｈ−イソキノリン−１−オン（５０ｍｇ、０．２ｍｍｏｌ）、ＨＡＴＵ（９９ｍｇ、０．２６ｍｍｏｌ）、３−（４−メチルフェニル）プロピオン酸（４２ｍｇ、０．２６ｍｍｏｌ）およびＤＩＰＥＡ（１１０ｍｇ、０．８６ｍｍｏｌ）を、塩化メチレン（３ｍＬ）中、室温で１６時間攪拌した。混合物をフラッシュクロマトグラフィー（１２ｇのシリカゲル、０〜１０％ＭｅＯＨ／ＣＨ２Ｃｌ２勾配）で精製し、Ｎ−［２−（２−ジメチルアミノ−エチル）−１−オキソ−１，２−ジヒドロ−イソキノリン−５−イル］−３−ｐ−トリル−プロピオンアミドを、白色固体（３１ｍｇ、０．０８ｍｍｏｌ、４０％）として得た。ＬＣ／ＭＳ（０．１％ギ酸変性剤）計算値（Ｍ＋１）^＋３７７．４８、測定値：３７８．２。

5-amino-2- (2-dimethylamino-ethyl) -2H-isoquinolin-1-one (50 mg, 0.2 mmol), HATU (99 mg, 0.26 mmol), 3- (4-methylphenyl) propionic acid ( 42 mg, 0.26 mmol) and DIPEA (110 mg, 0.86 mmol) were stirred in methylene chloride (3 mL) at room temperature for 16 hours. The mixture was purified by flash chromatography (12 g silica gel, 0-10% MeOH / CH2Cl2 gradient) and N- [2- (2-dimethylamino-ethyl) -1-oxo-1,2-dihydro-isoquinoline-5. -Il] -3-p-tolyl-propionamide was obtained as a white solid (31 mg, 0.08 mmol, 40%). LC / MS (0.1% formic acid modifier) calculated (M + 1) ⁺ 377.48, found: 378.2.

Ｎ−［２−（２−ジメチルアミノ−エチル）−１−オキソ−１，２−ジヒドロ−イソキノリン−５−イル］−２−ｐ−トリル−アセタミドの調製

Preparation of N- [2- (2-dimethylamino-ethyl) -1-oxo-1,2-dihydro-isoquinolin-5-yl] -2-p-tolyl-acetamide

５−アミノ−２−（２−ジメチルアミノ−エチル）−２Ｈ−イソキノリン−１−オン（５０ｍｇ、０．２ｍｍｏｌ）、ＨＡＴＵ（９９ｍｇ、０．２６ｍｍｏｌ）、ｐ−トリル酢酸（３９ｍｇ、０．２６ｍｍｏｌ）およびＤｌＰＥＡ（１１０ｍｇ、０．８６ｍｍｏｌ）を、塩化メチレン（３ｍＬ）中、室温で１８時間攪拌した。混合物を、フラッシュクロマトグラフィー（１２ｇのシリカゲル、０〜１０％ＭｅＯＨ／ＣＨ_２Ｃｌ_２勾配）で精製し、Ｎ−［２−（２−ジメチルアミノ−エチル）−１−オキソ−１，２−ジヒドロ−イソキノリン−５−イル］−２−ｐ−トリル−アセトアミドを、白色固体（２０ｍｇ、０．０５５ｍｍｏｌ、２７％）として得た。

5-amino-2- (2-dimethylamino-ethyl) -2H-isoquinolin-1-one (50 mg, 0.2 mmol), HATU (99 mg, 0.26 mmol), p-tolylacetic acid (39 mg, 0.26 mmol) And DlPEA (110 mg, 0.86 mmol) were stirred in methylene chloride (3 mL) at room temperature for 18 hours. The mixture was purified by flash chromatography (12 g silica gel, 0-10% MeOH / CH ₂ Cl ₂ gradient) and N- [2- (2-dimethylamino-ethyl) -1-oxo-1,2-dihydro -Isoquinolin-5-yl] -2-p-tolyl-acetamide was obtained as a white solid (20 mg, 0.055 mmol, 27%).

LC / MS (0.1% formic acid modifier) calculated (M + 1) ⁺ 363.45, found: 364.5.

Ｎ−置換−１−オキソ−１，２−ジヒドロ−イソキノリン−５−イル誘導体の代替の代表的調製法

Alternative exemplary preparation of N-substituted-1-oxo-1,2-dihydro-isoquinolin-5-yl derivatives

０．０８９ｍｍｏｌのピロンおよび６倍過剰のアミンを使用して反応を行った。全ての反応の完了を、ＬＣ／ＭＳでモニターし、完了すると、０．１％ギ酸緩衝液を用いて分取ＨＰＬＣで精製した。本発明のＮ−Ｌ^１−Ｒ^３置換化合物（ここで、Ｌ^１−Ｒ^３は、式Ｉで記載した通りである）は、特に他に記載がない限り、方法Ｂ１またはその変性法で記載した方法に類似の方法で調製しするか、または調製することができる。

The reaction was performed using 0.089 mmol of pyrone and a 6-fold excess of amine. The completion of all reactions was monitored by LC / MS and upon completion was purified by preparative HPLC using 0.1% formate buffer. The NL ¹ -R ³ substituted compounds of the present invention (wherein L ¹ -R ³ is as described in Formula I) are described in Method B1 or a modification thereof unless otherwise noted. Or can be prepared in a manner similar to that described.

Typical synthesis method Method A
(Compound 1006)
N- [2- (2-Dimethylamino-ethyl) -1-oxo-1,2-dihydro-isoquinolin-5-yl] -benzamide

ａ．２−（２−ジメチルアミノ−エチル）−５−ニトロ−２Ｈ−イソキノリン−１−オン
５−ニトロ−イソクロメン−１−オン（１．８３ｇ、０．００９５７ｍｏｌ）およびＮ，Ｎ−ジメチル−１，２−エタンジアミン（３ｇ、０．０３ｍｏｌ）を、メタノール（２０ｍＬ、０．５ｍｏｌ）中で１時間還流した。揮発物質をロータリーエバポレーターで除去した。残渣をフラッシュクロマトグラフィー（４０ｇのシリカゲル、５０％ＥｔＯＡｃ／ＣＨ_２Ｃｌ_２）で精製し、薄黄色固体を得た。
ＭＳ ｍ／ｚ（Ｍ＋Ｈ）２６２．３。

a. 2- (2-Dimethylamino-ethyl) -5-nitro-2H-isoquinolin-1-one 5-nitro-isochromen-1-one (1.83 g, 0.00957 mol) and N, N-dimethyl-1,2 Ethanediamine (3 g, 0.03 mol) was refluxed in methanol (20 mL, 0.5 mol) for 1 hour. Volatiles were removed on a rotary evaporator. The residue was purified by flash chromatography (40 g silica gel, 50% EtOAc / CH ₂ Cl ₂ ) to give a pale yellow solid.
MS m / z (M + H) 262.3.

b. 5-amino-2- (2-dimethylamino-ethyl) -2H-isoquinolin-1-one 2- (2-dimethylamino-ethyl) -5-nitro-2H-isoquinolin-1-one (1.10 g, 0 .00358 mol) was dissolved in MeOH (30 mL), Pd / C (10%) was added and the mixture was stirred at room temperature for 1 h under hydrogen atmosphere. The mixture was filtered through celite and the solvent removed in vacuo to give the title product as a pale yellow solid (0.82 g). MS m / z (M + H) 232.4.

c. N- [2- (2-Dimethylamino-ethyl) -1-oxo-1,2-dihydro-isoquinolin-5-yl] -benzamide 5-amino-2- (2-dimethylamino-ethyl) -2H-isoquinoline -1-one (50 mg, 0.0002 mol), benzoyl chloride (36 mg, 0.00026 mol) and N, N-diisopropylethylamine (110 mg, 0.00086 mol) in methylene chloride (3 mL, 0.05 mol) at room temperature. Stir for 2 hours. The mixture is diluted with CH ₂ Cl ₂ (20 mL), the organic layer is separated, washed with NaHCO ₃ (10 mL), dried over Na ₂ SO ₄ and flash column chromatography (12 g silica gel, 10% MeOH / Purification with CH ₂ Cl ₂ ) gave the product as a pale yellow solid.

方法Ｂ
（化合物１０１３）
２−シクロヘプチル−Ｎ−［２−（２，３−ジヒドロ−ベンゾ［１，４］ジオキシン−６−イルメチル）−１−オキソ−１，２−ジヒドロ−イソキノリン−５−イル］−アセトアミド

Method B
(Compound 1013)
2-cycloheptyl-N- [2- (2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) -1-oxo-1,2-dihydro-isoquinolin-5-yl] -acetamide

ａ．２−（２，３−ジヒドロ−ベンゾ［１，４］ジオキシン−６−イルメチル）−５−ニトロ−２Ｈ−イソキノリン−１−オン
５−ニトロ−イソクロメン−１−オン（１．０ｇ、０．００５２ｍｏｌ）およびＣ−（２，３−ジヒドロ−ベンゾ［１，４］ジオキシン−６−イル）−メチルアミン（１．０ｇ、０．００６０ｍｏｌ）を、メタノール（４０ｍＬ、１ｍｏｌ）中で２時間還流した。溶媒を除去し、残渣をフラッシュクロマトグラフィー（４０ｇのシリカゲル、０〜３０％ＥｔＯＡｃ／ヘキサン）で精製し、黄色固体を得た。
ＭＳ ｍ／ｚ（Ｍ＋Ｈ）３３９．５
ｂ．５−アミノ−２−（２，３−ジヒドロ−ベンゾ［１，４］ジオキシン−６−イルメチル）−２Ｈ−イソキノリン−１−オン
２−（２，３−ジヒドロ−ベンゾ［１，４］ジオキシン−６−イルメチル）−５−ニトロ−２Ｈ−イソキノリン−１−オン（０．９ｇ、０．００２ｍｏｌ）、二塩化スズ二水和物（２ｇ、０．００９ｍｏｌ）を、テトラヒドロフラン（１０ｍＬ、０．１ｍｏｌ）中、室温で２０時間攪拌した。揮発物質を除去し、残渣を、フラッシュカラムクロマトグラフィー（４０ｇのシリカゲル、５０％ＥｔＯＡｃ／ヘキサン）で精製し、赤色油状物を得た。ＭＳ ｍ／ｚ（Ｍ＋Ｈ）３０９．４。

a. 2- (2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl) -5-nitro-2H-isoquinolin-1-one 5-nitro-isochromen-1-one (1.0 g, 0.0052 mol) ) And C- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -methylamine (1.0 g, 0.0060 mol) were refluxed in methanol (40 mL, 1 mol) for 2 hours. The solvent was removed and the residue was purified by flash chromatography (40 g silica gel, 0-30% EtOAc / hexanes) to give a yellow solid.
MS m / z (M + H) 339.5
b. 5-Amino-2- (2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) -2H-isoquinolin-1-one 2- (2,3-dihydro-benzo [1,4] dioxin- 6-ylmethyl) -5-nitro-2H-isoquinolin-1-one (0.9 g, 0.002 mol), tin dichloride dihydrate (2 g, 0.009 mol), tetrahydrofuran (10 mL, 0.1 mol) The mixture was stirred at room temperature for 20 hours. Volatiles were removed and the residue was purified by flash column chromatography (40 g silica gel, 50% EtOAc / hexanes) to give a red oil. MS m / z (M + H) 309.4.

c. 2-Cycloheptyl-N- [2- (2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) -1-oxo-1,2-dihydro-isoquinolin-5-yl] -acetamide 5- Amino-2- (2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) -2H-isoquinolin-1-one (50 mg, 0.0002 mol), 2-cycloheptylacetic acid (63 mg, 0.00041 mol) ), Fluoro-N, N, N ′, N′-tetramethylformamidinium hexafluorophosphate (110 mg, 0.00041 mol) and N, N-diisopropylethylamine (100 mg, 0.0008 mol) were added to methylene chloride (3 mL, 0.05 mol) at room temperature for 72 hours. The mixture was purified by flash chromatography (12 g silica gel, 50% EtOAc / hexanes) to give a pale yellow solid.

方法Ｃ
（化合物１０２４）
２−シクロヘプチル−Ｎ−（２−メチル−１−オキソ−１，２−ジヒドロ−イソキノリン−５−イル）−アセトアミド

Method C
(Compound 1024)
2-Cycloheptyl-N- (2-methyl-1-oxo-1,2-dihydro-isoquinolin-5-yl) -acetamide

ａ．２−メチル−５−ニトロ−２Ｈ−イソキノリン−１−オン
５−ニトロ−イソクロメン−１−オン（１．２ｇ、０．００６３ｍｏｌ）および４０％メチルアミン水溶液（１０ｍＬ、０．０９ｍｏｌ）を、メタノール（４０ｍＬ、１ｍｏｌ）中で１時間、還流した。溶媒を除去し、残渣をＣＨ_２Ｃｌ_２／ＭｅＯＨ（９５：５ｖ／ｖ、１００ｍＬ）で希釈し、塩水（２０ｍＬ×２）で洗浄した。ＣＨ_２Ｃｌ_２層をＮａ_２ＳＯ_４で乾燥し、フラッシュクロマトグラフィー（４０ｇのシリカゲル、０〜５０％ＥｔＯＡｃ／ヘキサン）で精製し、黄色固体を得た。ＭＳ ｍ／ｚ（Ｍ＋Ｈ）２０４．８。

a. 2-Methyl-5-nitro-2H-isoquinolin-1-one 5-nitro-isochromen-1-one (1.2 g, 0.0063 mol) and 40% aqueous methylamine (10 mL, 0.09 mol) were added to methanol ( The mixture was refluxed for 1 hour in 40 mL, 1 mol). The solvent was removed and the residue was diluted with CH ₂ Cl ₂ / MeOH (95: 5 v / v, 100 mL) and washed with brine (20 mL × 2). The CH ₂ Cl ₂ layer was dried over _Na 2 SO _4, and purified by flash chromatography (40 g silica gel, 0 to 50% EtOAc / hexanes) to give a yellow solid. MS m / z (M + H) 204.8.

b. 5-Amino-2-methyl-2H-isoquinolin-1-one 2-Methyl-5-nitro-2H-isoquinolin-1-one (0.69 g, 0.0032 mol) and tin dichloride dihydrate (2 g, 0.01 mol) was stirred in tetrahydrofuran (10 mL, 0.1 mol) overnight at room temperature. The mixture was purified by flash chromatography (40 g silica gel, 50% EtOAc / hexanes) to give a brown solid. MS m / z (M + H) 174.9.

c. 2-Cycloheptyl-N- (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl) acetamide 5-amino-2-methyl-2H-isoquinolin-1-one (50 mg, 0.0003 mol) 2-cycloheptylacetic acid (90 mg, 0.0006 mol), fluoro-N, N, N ′, N′-tetramethylformamidinium hexafluorophosphate (200 mg, 0.0006 mol), N, N-diisopropylethylamine (100 mg) , 0.0009 mol) was stirred in methylene chloride (2 mL, 0.03 mol) at room temperature for 72 hours. The mixture was purified by flash chromatography (12 g silica gel, 0-50% EtOAc / hexanes) to give a yellow solid.

方法Ｄ
（化合物１３７３）
２−シクロヘプチル−Ｎ−［１−オキソ−２−（テトラヒドロ−ピラン−４−イルメチル）−１，２−ジヒドロ−イソキノリン−５−イル］−アセトアミド

Method D
(Compound 1373)
2-Cycloheptyl-N- [1-oxo-2- (tetrahydro-pyran-4-ylmethyl) -1,2-dihydro-isoquinolin-5-yl] -acetamide

ａ．５−ニトロ−２−（テトラヒドロ−ピラン−４−イルメチル）−２Ｈ−イソキノリン−１−オン
５−ニトロ−イソクロメン−１−オン（１．０ｇ、０．００５２ｍｏｌ）およびＣ−（テトラヒドロ−ピラン−４−イル）−メチルアミン（０．７２ｇ、０．００６３ｍｏｌ）を、１，４−ジオキサン（３ｍＬ、０．０４ｍｏｌ）中、１２０℃で１８時間攪拌した。混合物を、ＥｔＯＡｃ（２００ｍＬ）で希釈し、１ＮのＨＣｌ（３０ｍＬ×２）および塩水（３０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥した。ろ過後、溶媒を除去し、残渣をフラッシュクロマトグラフィー（４０ｇのシリカゲル、４０％ＥｔＯＡｃ／ヘキサン）で精製し、黄色油状物を得た。ＭＳ ｍ／ｚ（Ｍ＋Ｈ）２８９．１。

a. 5-Nitro-2- (tetrahydro-pyran-4-ylmethyl) -2H-isoquinolin-1-one 5-nitro-isochromen-1-one (1.0 g, 0.0052 mol) and C- (tetrahydro-pyran-4 -Yl) -methylamine (0.72 g, 0.0063 mol) was stirred in 1,4-dioxane (3 mL, 0.04 mol) at 120 ° C. for 18 hours. The mixture was diluted with EtOAc (200 mL), washed with 1N HCl (30 mL × 2) and brine (30 mL), and dried over Na ₂ SO ₄ . After filtration, the solvent was removed and the residue was purified by flash chromatography (40 g silica gel, 40% EtOAc / hexanes) to give a yellow oil. MS m / z (M + H) 289.1.

b. 5-Amino-2- (tetrahydro-pyran-4-ylmethyl) -2H-isoquinolin-1-one 5-nitro-2- (tetrahydro-pyran-4-ylmethyl) -2H-isoquinolin-1-one (0.78 g , 0.0027 mol) and tin dichloride dihydrate (2 g, 0.01 mol) were stirred in tetrahydrofuran (10 mL, 0.1 mol) at room temperature for 24 hours. The mixture was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO ₃ and separated. The aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na ₂ SO ₄ and purified by flash chromatography (40 g silica gel, 0-100% EtOAc / hexanes) to give a yellow solid. MS m / z (M + H) 259.2.

c. 2-cycloheptyl-N- [1-oxo-2- (tetrahydro-pyran-4-ylmethyl) -1,2-dihydro-isoquinolin-5-yl) -acetamide 5-amino-2- (tetrahydro-pyran-4 -Ylmethyl) -2H-isoquinolin-1-one (40 mg, 0.0002 mol), 2-cycloheptylacetic acid (63 mg, 0.00041 mol), fluoro-N, N, N ′, N′-tetramethylformamidinium hexa Fluorophosphate (110 mg, 0.00041 mol) and N, N-diisopropylethylamine (100 mg, 0.0008 mol) were stirred in methylene chloride (3 mL, 0.05 mol) at room temperature for 72 hours. The mixture was purified by flash chromatography (12 g silica gel, 0-50% EtOAc / hexanes) to give a pale yellow solid.

方法Ｅ
（化合物１３８０）
酢酸２−｛５−［２−（４−クロロ−３−トリフルオロメチル−フェニル）−アセチルアミノ］−１−オキソ−１Ｈ−イソキノリン−２−イル｝−エチルエステル

Method E
(Compound 1380)
Acetic acid 2- {5- [2- (4-chloro-3-trifluoromethyl-phenyl) -acetylamino] -1-oxo-1H-isoquinolin-2-yl} -ethyl ester

ａ．２−（２−ヒドロキシエチル）−５−ニトロイソキノリン−１（２Ｈ）−オン
５−ニトロ−イソクロメン−１−オン（３．６０ｇ、０．０１７０ｍｏｌ）を、メタノール（４０ｍＬ）に懸濁し、エタノールアミン（３．１１ｇ、０．０５０８ｍｏｌ）を加え、反応混合物を７０℃で２時間、窒素雰囲気下で攪拌した。混合物を室温まで冷却し、トリエチルアミン（５ｍＬ）を加えた。反応混合物を室温で週末中（２日間）攪拌した。このようにして形成した固体をろ取した（黄色固体を目的生成物０．９ｇとして得た）。ろ液を濃縮し、残渣を酢酸エチルに溶解し、水およびブラインで洗浄し、硫酸ナトリウムで乾燥し、溶媒を除去し、生成物を黄色固体（１．３ｇ）として得た。

a. 2- (2-hydroxyethyl) -5-nitroisoquinolin-1 (2H) -one 5-nitro-isochromen-1-one (3.60 g, 0.0170 mol) was suspended in methanol (40 mL) and ethanolamine was added. (3.11 g, 0.0508 mol) was added and the reaction mixture was stirred at 70 ° C. for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and triethylamine (5 mL) was added. The reaction mixture was stirred at room temperature over the weekend (2 days). The solid thus formed was collected by filtration (a yellow solid was obtained as 0.9 g of the desired product). The filtrate was concentrated and the residue was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and the solvent was removed to give the product as a yellow solid (1.3 g).

b. 2- (5-Nitro-1-oxoisoquinolin-2 (1H) -yl) ethyl acetate 2- (2-hydroxyethyl) -5-nitroisoquinolin-1 (2H) -one (2.2 g, 0.0089 mol) Is dissolved in a mixture of dichloromethane (20 mL) and dimethylformamide (10 mL), N, N-diisopropylethylamine (2.33 mL, 0.0134 mol) and acetyl chloride (1.06 g, 0.0134 mol) are added and the reaction mixture is added. Was stirred at room temperature for 30 minutes. Volatiles were removed and the residue was washed with water then diethyl ether to give a pale yellow solid (2.45 g). MS m / z = 276.5 (M + H).

c. 2- (5-Amino-1-oxoisoquinolin-2H) -yl) ethyl acetate of 2- (5-nitro-1-oxoisoquinolin-2 (1H) -yl) ethyl acetate (2.45 g, 0.00842 mol) The mixture was dissolved in methanol (100 mL), and palladium on carbon (10%) was stirred under a hydrogen atmosphere for 1 hour. The mixture was filtered through celite and the solvent was removed to give the product as a pale orange solid (1.98 g). MS m / z = 248.0 (M + H).

d. Acetic acid 2-5- [2- (4-chloro-3-trifluoromethyl-phenyl) -acetylamino] -1-oxo-1 # H! -Isoquinolin-2-yl-ethyl ester A solution of 2- (4-chloro-3- (trifluoromethyl) phenyl) acetic acid (131 mg, 0.000548 mol) in thionyl chloride (5 mL) was stirred at 60 ° C for 1 hour. Thionyl chloride was removed and the residue was dissolved in tetrahydrofuran (5 mL). 2- (5-Amino-1-oxoisoquinolin-2 (1H) -yl) ethyl acetate (100.0 mg, 0.0003655 mol) and N, N-diisopropylethylamine (95.5 uL, 0.000548 mol) in THF solution. In addition, the reaction mixture was stirred at room temperature for 1 hour. Volatiles were removed and the residue was dissolved in ethyl acetate and washed with water, 2N HCl and brine. The combined organic layers were dried over sodium sulfate and the solvent was removed. The residue was purified on a column to give the product as a beige solid (65 mg). MS m / z = 467.0 (M + H).

方法Ｆ
（化合物１６２３）
２−（４−クロロ−３−トリフルオロメチル−フェニル）−Ｎ−［２−（２−メトキシ−エチル）−１−オキソ−１，２−ジヒドロ−イソキノリン−５−イル］−アセトアミド

Method F
(Compound 1623)
2- (4-Chloro-3-trifluoromethyl-phenyl) -N- [2- (2-methoxy-ethyl) -1-oxo-1,2-dihydro-isoquinolin-5-yl] -acetamide

ａ．２−（２−メトキシエチル）−５−ニトロイソキノリン−１（２Ｈ）−オン
丸底フラスコに、５−ニトロ−イソクロメン−１−オン（５．００ｇ、０．０２３５ｍｏｌ）、２−メトキシエチルアミン（６．１４ｍＬ、０．０７０６ｍｏｌ）およびメタノール（１５０ｍＬ、３．７ｍｏｌ）を合わせた。混合物を還流温度で１．５時間加熱した。混合物を室温まで冷却し、トリエチルアミン（６．５６ｍＬ、０．０４７１ｍｏｌ）を加えた。混合物を室温で一晩攪拌した。ＬＣ−ＭＳにより、出発物質が完全に消費されたことが示された。過剰のトリエチルアミンおよび酢酸エチルを加え、混合物を室温で３０分間攪拌した。黄色析出物が形成され、これをろ過し、ろ液を濃縮し、黄色固体を得た。合わせた固体を、さらに精製することなく、次の工程に使用した。

a. 2- (2-methoxyethyl) -5-nitroisoquinolin-1 (2H) -one To a round bottom flask was added 5-nitro-isochromen-1-one (5.00 g, 0.0235 mol), 2-methoxyethylamine (6 .14 mL, 0.0706 mol) and methanol (150 mL, 3.7 mol) were combined. The mixture was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and triethylamine (6.56 mL, 0.0471 mol) was added. The mixture was stirred overnight at room temperature. LC-MS showed that the starting material was completely consumed. Excess triethylamine and ethyl acetate were added and the mixture was stirred at room temperature for 30 minutes. A yellow precipitate was formed, which was filtered and the filtrate was concentrated to give a yellow solid. The combined solid was used in the next step without further purification.

b. 5-Amino-2- (2-methoxyethyl) isoquinolin-1 (2H) -one In a 250 ml round bottom flask was added 2- (2-methoxyethyl) -5-nitroisoquinolin-1 (2H) -one (1.23 g). , 0.00495 mol), palladium / C (0.05 g, 0.0005 mol) and methanol (50 mL, 1 mol). The flask was purged and degassed twice with hydrogen and the mixture was stirred under a hydrogen atmosphere (1 atm) for 2 hours. The mixture was filtered through celite and the filtrate was reduced in vacuo to give the title compound as a light brown solid.

c. 2- (4-Chloro-3- (trifluoromethyl) phenyl) -N- (1,2-dihydro-2- (2-methoxyethyl) -1-oxoisoquinolin-5-yl) acetamide in a 20 ml reaction vial, 5-amino-2- (2-methoxyethyl) isoquinolin-1 (2H) -one (0.020 g, 0.000087 mol), 2- (4-chloro-3- (trifluoromethyl) phenyl) acetic acid (31 mg, 0.00013 mol), N, N, N ′, N′-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (81.66 mg, 0.0002148 mol), N, N— Diisopropylethylamine (69.2 uL, 0.000397 mol) and N, N-dimethylformamide (1 mL, 0.02 ol) were combined. The mixture was heated at 40 ° for 12 hours. The reaction was allowed to cool and poured into saturated sodium bicarbonate (200 ml). The mixture was extracted with ethyl acetate (3 × 100 ml). The combined extracts were dried with sodium sulfate and reduced in vacuo. The remaining residue was purified by reverse phase preparative HPLC at pH 10 using an acetonitrile: water gradient. The combined pure fractions were reduced in vacuo to give the compound as an off-white solid. LC_MS (M + H) = 439.2.

Method G
(Compound 1624)
2- (4-Chloro-3-trifluoromethyl-phenyl) -N- [1-oxo-2- (6-trifluoromethyl-pyridin-3-ylmethyl) -1,2-dihydro-isoquinolin-5-yl ] -Acetamide

ａ．２−（（６−（トリフルオロメチル）ピリジン−３−イル）メチル）−５−ニトロイソキノリン−１（２Ｈ）−オン
Ｃ−（６−トリフルオロメチル−ピリジン−３−イル）−メチルアミン（１．００ｇ、０．００５６８ｍｏｌ）および５−ニトロ−イソクロメン−１−オン（１．１４ｇ、０．００５６８ｍｏｌ）を、メタノール（１０ｍＬ）に懸濁し、懸濁液を６０℃で３時間攪拌し、次いで反応系を１００ワット、１００℃で６０分間、次いでｌ２０℃で３０分間、マイクロ波に曝した。このようにして形成された固体をろ取し、生成物を黄色固体（１．２ｇ）として得た。ＭＳ ｍ／ｚ＝３５０．４（Ｍ＋Ｈ）。

a. 2-((6- (trifluoromethyl) pyridin-3-yl) methyl) -5-nitroisoquinolin-1 (2H) -one C- (6-trifluoromethyl-pyridin-3-yl) -methylamine ( 1.00 g, 0.00568 mol) and 5-nitro-isochromen-1-one (1.14 g, 0.00568 mol) are suspended in methanol (10 mL) and the suspension is stirred at 60 ° C. for 3 hours, then The reaction was exposed to microwave at 100 watts, 100 ° C. for 60 minutes, then 120 ° C. for 30 minutes. The solid thus formed was collected by filtration to give the product as a yellow solid (1.2 g). MS m / z = 350.4 (M + H).

b. 5-amino-2-((6- (trifluoromethyl) pyridin-3-yl) methyl) isoquinolin-1 (2H) -one palladium on carbon (10%) was converted to 2-((6- (trifluoromethyl ) Pyridin-3-yl) methyl) -5-nitroisoquinolin-1 (2H) -one (1.16 g, 0.00315 mol) in methanol (30 mL) was added and the mixture was stirred under a hydrogen atmosphere for 40 minutes. The mixture was filtered through celite. The filtrate was concentrated and the residue was purified on a column to give the product as a beige solid (0.83 g). MS m / z = 320.3 (M + H).

c. 2- (4-Chloro-3- (trifluoromethyl) phenyl) -N- (2-((6- (trifluoromethyl) pyridin-3-yl) methyl) -1,2-dihydro-1-oxoisoquinoline 5-yl) acetamide 2- (4-Chloro-3- (trifluoromethyl) phenyl) acetic acid (142 mg, 0.000595 mol) was dissolved in thionyl chloride (10 mL) and the mixture was stirred at 60 ° C. for 3 hours. Volatiles were removed and the residue was dissolved in tetrahydrofuran. 5-Amino-2-((6- (trifluoromethyl) pyridin-3-yl) methyl) isoquinolin-1 (2H) -one (100.0 mg, 0.0002975 mol) and N, N-diisopropylethylamine (0. 104 mL, 0.000595 mol) was added and the mixture was stirred at room temperature for 1 hour. Methanol was added to quench the reaction and remove volatiles. The residue was dissolved in ethyl acetate, washed with water, sodium carbonate solution and brine, and purified on a column to give the product as a beige solid (120 mg). MS m / z = 540.4 (M + H).

方法Ｈ
（化合物１６２８）
２−（４−クロロ−３−トリフルオロメチル−フェニル）−Ｎ−（ｌ−オキソ−２−ピリジン−２−イルメチル−１，２−ジヒドロ−イソキノリン−５−イル）−アセトアミド

Method H
(Compound 1628)
2- (4-Chloro-3-trifluoromethyl-phenyl) -N- (l-oxo-2-pyridin-2-ylmethyl-1,2-dihydro-isoquinolin-5-yl) -acetamide

ａ．５−ニトロ−２−（ピリジン−２−イルメチル）イソキノリン−１−（２Ｈ）−オン
マイクロ波バイアルに、５−ニトロ−イソクロメン−１−オン（１ｇ、０．００５ｍｏｌ）、２−ピリジンメタンアミン（１ｇ、０．００９ｍｏｌ）およびメタノール（２０ｍＬ、０．５ｍｏｌ）を合わせた。混合物を１５０℃で２時間加熱した。混合物を室温まで冷却した。反応混合物に対し通常の処理を施し、粗生成物を得、次いで、これをシリカゲル上でのフラッシュクロマトグラフィーを使用して精製し、純生成物を黄色固体（０．７ｇ）として得た。ＭＳ ｍ／ｚ＝２８２．４（Ｍ＋１）。

a. 5-Nitro-2- (pyridin-2-ylmethyl) isoquinolin-1- (2H) -one A microwave vial was charged with 5-nitro-isochromen-1-one (1 g, 0.005 mol), 2-pyridinemethanamine ( 1 g, 0.009 mol) and methanol (20 mL, 0.5 mol) were combined. The mixture was heated at 150 ° C. for 2 hours. The mixture was cooled to room temperature. The reaction mixture was treated normally to give the crude product which was then purified using flash chromatography on silica gel to give the pure product as a yellow solid (0.7 g). MS m / z = 282.4 (M + l).

b. 5-Amino-2- (pyridin) -2-ylmethyl) isoquinolin-1 (2) one In a round bottom flask, add 5-nitro-2- (pyridin-2-ylmethyl) isoquinolin-1 (2H) -one (0. 7 g, 0.002 mol), palladium / C (0.05 g, 0.0005 mol) and methanol (200 mL, 5 mol) were combined. The reaction mixture was stirred under a hydrogen balloon at room temperature for 40 minutes. The mixture was filtered through celite to remove MeOH to give a solid (0.46 mg). MS m / z = 252.4 (M + l).

ｃ．２−（４−クロロ−３−（トリフルオロメチル）フェニル）−Ｎ−（１−オキソ−２−（ピリジン−２−イルメチル）−１，２−ジヒドロイソキノリン−５−イル）−アセトアミド
５−アミノ−２−（ピリジン−２−イルメチル）イソキノリン−１（２Ｈ）−オン（１００．００ｍｇ、０．４ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．７ｍＬ、０．００９ｍｏｌ）溶液に、２−（４−クロロ−３−（トリフルオロメチル）フェニル）酢酸（１９０ｍｇ、０．０００７９６ｍｏｌ）、Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチル−Ｏ−（７−アザベンゾトリアゾール−１−イル）ウロニウムヘキサフルオロホスフェート（３０３ｍｇ、０．０００７９６ｍｏｌ）およびＮ，Ｎ−ジイソプロピルエチルアミン（２７７ｕＬ、０．００１５９ｍｏｌ）を加えた。反応混合物を、５０℃で１６時間攪拌した。ＬＣ／ＭＳで反応が完了したことを調べた。ＤＭＦ反応溶液を、直接分取ＨＰＬＣに供し、純粋な生成物（１３４．２ｍｇ）を得た。ＭＳ ｍ／ｚ＝４７２．３（Ｍ＋１）。

c. 2- (4-Chloro-3- (trifluoromethyl) phenyl) -N- (1-oxo-2- (pyridin-2-ylmethyl) -1,2-dihydroisoquinolin-5-yl) -acetamide 5-amino To a solution of 2- (pyridin-2-ylmethyl) isoquinolin-1 (2H) -one (100.00 mg, 0.4 mmol) in N, N-dimethylformamide (0.7 mL, 0.009 mol), 2- (4 -Chloro-3- (trifluoromethyl) phenyl) acetic acid (190 mg, 0.000796 mol), N, N, N ', N'-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexa Fluorophosphate (303 mg, 0.000796 mol) and N, N-diisopropylethylamine (277 uL, 0.00159 mol) The added. The reaction mixture was stirred at 50 ° C. for 16 hours. It was checked by LC / MS that the reaction was complete. The DMF reaction solution was directly subjected to preparative HPLC to give a pure product (134.2 mg). MS m / z = 472.3 (M + l).

方法Ｊ
（化合物１６３０）
２−（４−クロロ−３−トリフルオロメチル−フェニル）−Ｎ−［２−（２−メタンスルホニル−エチル）−１−オキソ−１，２−ジヒドロ−イソキノリン−５−イル］−アセタミド

Method J
(Compound 1630)
2- (4-Chloro-3-trifluoromethyl-phenyl) -N- [2- (2-methanesulfonyl-ethyl) -1-oxo-1,2-dihydro-isoquinolin-5-yl] -acetamide

ａ．２−（２−（メチルスルホニル）エチル）−５−ニトロイソキノリン−１（２Ｈ）−オン
丸底フラスコで、５−ニトロ−イソクロメン−１−オン（１．５ｇ、０．００７１ｍｏｌ）、２−（メチルスルホニル）エタンアミド塩酸塩（２．２ｇ、０．０１４ｍｏｌ）およびメタノール（４５ｍＬ、１．１ｍｏｌ）を合わせた。混合物を還流で１．５時間加熱した。混合物を室温まで冷却し、濃縮し、黄色固体を得た。固体を、さらに精製することなく、次の工程に使用した。

a. 2- (2- (Methylsulfonyl) ethyl) -5-nitroisoquinolin-1 (2H) -one In a round bottom flask, 5-nitro-isochromen-1-one (1.5 g, 0.0071 mol), 2- ( Methylsulfonyl) ethaneamide hydrochloride (2.2 g, 0.014 mol) and methanol (45 mL, 1.1 mol) were combined. The mixture was heated at reflux for 1.5 hours. The mixture was cooled to room temperature and concentrated to give a yellow solid. The solid was used in the next step without further purification.

b. 5-Amino-2- (2- (methylsulfonyl) ethyl) isoquinolin-1 (2H) -one In a 250 mL round bottom flask, add 2- (2- (methylsulfonyl) ethyl) -5-nitroisoquinoline-1 (2H). -Combined with on (1.20 g, 0.00405 mol), palladium / C (0.04 g, 0.0004 mol) and methanol (40 mL, 1 mol). The flask was evacuated three times and purged with hydrogen. The mixture was stirred at room temperature under hydrogen (1 atm) for 3 hours. The mixture was filtered through celite and the filtrate was reduced in vacuo. The mixture was purified by column chromatography using a methanol: methylene chloride (0-10%) gradient. The combined pure fractions were reduced in vacuo to give the title compound as an off-white solid.

c. 2- (4-Chloro-3- (trifluoromethyl) phenyl) -N- (2- (2- (methylsulfonyl) ethyl) -1-oxo-1,2-dihydroisoquinolin-5-yl) acetamide 5- To a solution of amino-2- (2- (methylsulfonyl) ethyl) isoquinolin-1 (2H) -one (30 mg, 0.0001 mol) in N, N-dimethylformamide (700 μL, 0.009 mol), 2- (4- Chloro-3- (trifluoromethyl) phenyl) acetic acid (51 mg, 0.00021 mol), N, N, N ′, N′-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluoro Phosphate (102 mg, 0.000268 mol) and N, N-diisopropylethylamine (93 μL, 0.00054 mol) added. The reaction mixture was stirred at 50 ° C. for 16 hours. LC-MS analysis indicated that the desired product was formed. The mixture was taken up in saturated NaHCO ₃ solution and washed twice with ethyl acetate. The organic layer was dried over sodium sulfate, reduced in vacuo and purified by HPLC to give the title compound as a white solid.

方法Ｋ
（化合物１６３３）
２−（２−フルオロ−３−トリフルオロメチル−フェニル）−Ｎ−［１−オキソ−２−（１−ピリジン−２−イル−エチル）−１，２−ジヒドロ−イソキノリン−５−イル］−アセトアミド

Method K
(Compound 1633)
2- (2-Fluoro-3-trifluoromethyl-phenyl) -N- [1-oxo-2- (1-pyridin-2-yl-ethyl) -1,2-dihydro-isoquinolin-5-yl]- Acetamide

ａ．５−ニトロ−２−（１−（ピリジン−２−イル）エチル）イソキノリン−１（２Ｈ）オン
マイクロ波バイアルに、５−ニトロ−イソクロメン−１−オン（１ｇ、０．００５ｍｏｌ）、１−ピリジン−２−イル−エチルアミン（１ｇ、０．００９ｍｏｌ）およびメタノール（２０ｍＬ、０．５ｍｏｌ）を合わせた。混合物を、１５０℃で２時間加熱した。混合物を室温まで冷却した。ＬＣ−ＭＳにより、出発物質が完全に消費されたことが示された。シリカゲルカラム後、黄色固体を得た（０．８５ｇ）。ＭＳ ｍ／ｚ＝２９５．９（Ｍ＋１）。

a. 5-Nitro-2- (1- (pyridin-2-yl) ethyl) isoquinolin-1 (2H) one In a microwave vial, 5-nitro-isochromen-1-one (1 g, 0.005 mol), 1-pyridine. 2-yl-ethylamine (1 g, 0.009 mol) and methanol (20 mL, 0.5 mol) were combined. The mixture was heated at 150 ° C. for 2 hours. The mixture was cooled to room temperature. LC-MS showed that the starting material was completely consumed. A yellow solid was obtained after the silica gel column (0.85 g). MS m / z = 295.9 (M + l).

b. 5-amino-2- (1- (pyridin-2-yl) ethyl) isoquinolin-1 (2H) -one In a round bottom flask, add 5-nitro-2- (1- (pyridin-2-yl) ethyl) isoquinoline. -1 (2H) -one (0.85 g, 0.0029 mol), palladium / C (0.05 g, 0.0005 mol) and methanol (200 mL, 5 mol) were combined. The reaction mixture was stirred under a hydrogen balloon at room temperature for 40 minutes. The mixture was filtered through celite to remove MeOH to give a solid (0.54 mg). MS m / z = 266.0 (M + l).

ｃ．２−（２−フルオロ−３−（トリフルオロメチル）フェニル）−Ｎ−（１−オキソ−２−（−１−（ピリジン−２−イル）エチル）−１，２−ジヒドロイソキノリン−５−イル）アセトアミド
５−アミノ−２−（ｌ−（ピリジン−２−イル）エチル）イソキノリン−１（２Ｈ）−オン（１００ｍｇ、０．０００４ｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１ｍＬ、０．０１ｍｏｌ）溶液に、２−（２−フルオロ−３−（トリフルオロメチル）フェニル）酢酸（１７８ｍｇ、０．０００８０１ｍｏｌ）、Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチル−Ｏ−（７−アザベンゾトリアゾール−１−イル）ウロニウムヘキサフルオロホスフェート（４６８．３ｍｇ、０．００１２３２ｍｏｌ）およびＮ，Ｎ−ジイソプロピルエチルアミン（３００ｕＬ、０．００２ｍｏｌ）を加えた。反応混合物を５０℃で１６時間攪拌した。ＬＣ／ＭＳは、反応が完了したことを示した。ＤＭＦ反応溶液を直接分取ＨＰＬＣに供した。最終生成物を、固体（１０２．４ｍｇ）として得た。ＭＳ ｍ／ｚ＝４７０．３（Ｍ＋１）。

c. 2- (2-Fluoro-3- (trifluoromethyl) phenyl) -N- (1-oxo-2-(-1- (pyridin-2-yl) ethyl) -1,2-dihydroisoquinolin-5-yl ) Acetamide N, N-dimethylformamide (1 mL, 0.01 mol) solution of 5-amino-2- (l- (pyridin-2-yl) ethyl) isoquinolin-1 (2H) -one (100 mg, 0.0004 mol) 2- (2-fluoro-3- (trifluoromethyl) phenyl) acetic acid (178 mg, 0.000801 mol), N, N, N ′, N′-tetramethyl-O- (7-azabenzotriazole-1 -Yl) uronium hexafluorophosphate (468.3 mg, 0.001232 mol) and N, N-diisopropylethylamine (300 uL, 0.0 2mol) was added. The reaction mixture was stirred at 50 ° C. for 16 hours. LC / MS indicated that the reaction was complete. The DMF reaction solution was directly subjected to preparative HPLC. The final product was obtained as a solid (102.4 mg). MS m / z = 470.3 (M + l).

（実施例１）
Ｐ２Ｘ_７レセプターは、Ｊ７７４（マウスマクロファージ株、Ａｍｅｒｉｃａｎ Ｔｙｐｅ Ｃｕｌｔｕｒｅ Ｃｏｌｌｅｃｔｉｏｎ（ＡＴＣＣ）、Ｒｏｃｋｖｉｌｌｅ、ＭＤ、ＡＴＣＣ ＴＩＢ−６７）、Ｐ３８８（マウス細胞株、ＡＴＣＣ ＣＣＬ−４６）、Ｐ８１５（マウスマスト細胞肥満細胞種由来株、ＡＴＣＣ ＴＩＢ−６４）、ＴＨＰ−１（ヒト単核細胞由来細胞株、ＡＴＣＣ ＴＩＢ２０２）およびＵ９３７（単核細胞分化を誘発し得る、組織球性リンパ腫に由来するヒト細胞株、ＡＴＣＣ ＣＲＬ−１５９３．２）を含む（しかし、これらに限定されない）マクロファージ由来細胞株において、そして単離されたマクロファージ培養物において強く発現する。ヒトまたは非ヒト動物のマクロファージは、以下に記載する手順により単離する。

Example 1
P2X ₇ receptors, J774 (mouse macrophage strain, American Type Culture Collection (ATCC) , Rockville, MD, ATCC TIB-67), P388 ( murine cell line, ATCC CCL-46), P815 ( murine mast cells mastocytoma-derived Strains, ATCC TIB-64), THP-1 (human mononuclear cell-derived cell line, ATCC TIB202) and U937 (human cell line derived from histiocytic lymphoma capable of inducing mononuclear cell differentiation, ATCC CRL-1593. .2) is strongly expressed in macrophage-derived cell lines including but not limited to and in isolated macrophage cultures. Human or non-human animal macrophages are isolated by the procedure described below.

P2Z / P2X ₇ receptor channel opening, for example, the measurement of ion flow and / or the receptor and monitoring the dye uptake or cell lysis in cells naturally expressing, be characterized by the evaluation of the pore forming it can. Compounds such as ATP, 2 ′ and 3 ′-(O)-(4-benzoylbenzoyl) ATP (BzATP) form pores at the plasma membrane of these cells, especially at low extracellular divalent ion concentrations. (Buisman et al., Proc. Natl. Acad. Sci. USA 85: 7988 (1988); Zambon et al., Cell. Immunol 156: 458 (1994); Hickman et al., Blood 84: 2452 (1994)). During cell recording, it can be seen that large molecule size dyes including the propidium dye YO-PRO-1 enter macrophage-derived cell lines (Hickman et al., Blood 84: 2452 (1994); Wiley et al., Br J Pharmacol 112). : 946 (1994); Steinberg et al., J Biol Chem 262: 8884 (1987)). If an increase in the fluorescence intensity of intracellular DNA-bound ethidium bromide is observed, ethidium bromide (a fluorescent DNA probe) can also be monitored. Expression of recombinant rat or human rP2X ₇ in cells, and Xenopus oocytes containing HEK293 cells, by whole cell recordings and YO-PRO-1 fluorescent intensity, demonstrating the flow rate and pore forming (Suprenant et, Science272: 735 (1996); Rassendren et al., J Biol Chem 272: 5482 (1997)).

The compounds of this invention are tested for antagonist activity at the P2X ₇ receptor. The tests performed include (i) electrophysiological experiments, (ii) YO-PRO1 fluorescence intensity, (iii) ethidium bromide fluorescence intensity, and (iv) IL-1β release from stimulated macrophages. Are selected from these. The compounds can be tested in vivo in animal models including inflammation models (eg, paw edema model, collagen-induced arthritis, MS EAE model).

(Isolation of human macrophages)
Mononuclear cell-derived human or non-human animal macrophage cultures are generated as described by Blanchard et al. (Blanchard et al., J Cell Biochem 57: 452 (1995); Blanchard et al., J Immunol 147: 2579 (1991)). Briefly, mononuclear cells are isolated from leukocyte concentrates obtained from healthy volunteers. Leukocytes are suspended in RPMI 1460 medium (Life Technologies) with 20% serum (human for human cells), 2 mM glutamine, 5 mM HEPES and 100 μg / ml streptomycin. Cells are allowed to adhere to the culture flask for 1-2 hours, after which unattached cells are washed away. Adherent cells are cultured in this medium + interferon-γ (human for human cells) (1000 units / ml) for 7-14 days. Macrophages are collected from culture flasks by pipetting with cold phosphate buffered saline and placed on electrophysiological coverslips or other experiments are performed 12-24 hours later.

(Example 2)
(Electrophysiological experiment)
Whole cell recording is performed using an EPC9 patch clamp amplifier and a pulse capture program (HEKA, Lambrecht, Germany). Whole cell recordings are obtained from cells such as J774A. 1 (American Type Culture Collection, Rockville, MD, ATCC TIB-67)), agonists are applied for 1-3 seconds by a high flow rate U-tube delivery system [E. M.M. Fenwick, A.M. Marty, E.M. Neher, J. et al. Physiol, (London) 331, 577 (1982)]. The internal pipette solution is 140 mM cesium-aspartate or potassium-aspartate, 20 mM NaCl, 10 mM EGTA and 5 mM Hepes; the standard external solution is 145 mM NaCl, 2 mM KCl, 2 mM CaCl ₂ a glucose 1mM of MgCl _2, 10 mM Hepes, and 12 mM. A low divalent external solution is 0.3 mM CaCl ₂ and is nominally free of magnesium. In a low divalent solution, the current in response to an agonist applied for 1 second is recorded at 8 minute intervals to create a concentration response curve, and a standard external solution is present for 6 minutes before each application. This protocol requires preventing the generation of persistent internal current.

The reversal potential (E _rev ) is obtained by application of ATP (300 μM) or BzATP (30 μM) (control), or the compound to be tested, while the membrane is kept at various potentials, or −120-30 or Keep by using a 50 mV voltage ramp. The permeation ratio was first determined for α (=) for internal (i) and external (o) concentrations, [Na] _i = 20 mM, [Na] _o = 145 mM, [K] _o = 0 mM and [K] _i = 140 mM. P _Na / P _K (where P is transmission)) and α = ([145 / exp (E _rev FIRT)] − 20) / 140 where F is a Faraday constant and R is Gas constant, and T is an absolute temperature). The other P _x / P _Na ratios are: [X] _o = 145 mM, [Na] _i = 20 mM, [K] _i = 140 mM and [Na] _o = [K] _o = [X] _i = 0 mM, P _x / P _Na = [(exp) E _rev F / RT] (20 + 140α)) / 145 In order of size, X is cesium, methylamine, Tris (hydroxymethyl) -aminomethane, tetraethylammonium, and N-methyl-D-glucamine. The internal solution also contains 10 mM EGTA and 5 mM Hepes. The external solution also contains 10 mM glucose and normal or low concentration of divalent cations, the pH is kept at 7.3 with HCl, histidine or Hepes as required, and the osmotic pressure of all solutions is 295 ~ 315.

(Example 3)
(YO-PRO1 fluorescence intensity)
A photonics image (IDEA) system (Photonics, Planegg, Germany) for microfluorescence measurement is used. The cover glass is placed on the pedestal of a Zeiss Axiovert 100 or equivalent inversion microscope and observed under oil immersion with a 40 × fluorescent objective lens. Before switching to a low divalent solution, YO-PRO-1 (10 μM; Molecular Probes, Eugene, OR) is added to the perfusion fluid for 3-6 minutes on the electrophysiological recording to obtain a normal divalent solution. When returning, wash off, then turn on the fluorescent lamp and evaluate the cells with a fluorescein isothiocyanate filter. YO-PRO1 fluorescence intensity is measured using a 491/509 nm excitation / emission wavelength. With YO-PROl, images are acquired at 5-20 second intervals during continuous perfusion (2 ml / min) and the concentrations of control ATP, BzATP or compound to be tested are varied. In each experiment, YO-PRO1 fluorescence intensity over time is obtained for 10-20 single cells and averaged to obtain an average fluorescence signal. Results relates rP2X _7, expressed as the mean signal at 3 minutes, the signal at 10 min is used in reference to P2X ₇ and human macrophage cells. All experiments are performed at room temperature.

Example 4
(Ethidium bromide)
The compounds of the present invention, by monitoring ethidium bromide entering the P2X ₇ receptor-expressing cells during pore formation, to test antagonist activity in P2X ₇ receptors. Test was carried out in 96-well flat bottom microtiter plate, the wells is a suspension of P2X ₇ expressing cells (e.g., THP-1 cells, J774 cells) (2.5 × 10 ⁶ cells / ml) 250 μl test containing 25 μl high potassium buffer containing 10 ⁻⁴ M ethidium bromide, 10 ⁻⁵ M BzATP, and 200 μl suspension containing 25 μl high potassium buffer containing test compound The solution is filled. Cover the plate with a plastic sheet and incubate at 37 ° C. for 1 hour. The plate is then read using a Perkin-Elmer fluorescent plate reader with excitation 520 nm, emission 595 nm, slit width: Ex 15 nm, EM 20 nm. For comparison, BzATP and (P2X ₇ receptor agonist) and pyridoxal 5-phosphate (P2X ₇ receptor agonist), as a control, used separately in the test. From the readings obtained, IC ₅₀ values for each test compound are calculated. This value is the negative logarithm of the concentration of test compound required to reduce BzATP agonist activity by 50%.

(Example 5)
(IL-1β release)
In this example illustrates the testing of the compounds of the present invention for efficacy as inhibitors of P2X ₇ mediated release of IL-l [beta] from activated human macrophages by Alzheimer-type β-amyloid peptide 1-42.

(Isolation of cells)
Mononuclear cells are isolated from peripheral blood mononuclear cells (PBMC) as follows. Whole blood is placed directly on a Histopak 1077-1 column (Sigma Biochemicals) and centrifuged at 800 × g for 15 minutes. Transfer the PBMC band of cells to a new 50 ml culture tube, dilute 1: 1 with wash buffer (containing phosphate buffered saline, pH 7.4, 2 mM EDTA and 5 mg / ml BSA), then Centrifuge for 5 minutes at 800 × g. The cells are then washed with a continuous resuspension of the cell pellet in wash buffer and centrifuged at 600 × g for 5 minutes. The washing process is repeated until the supernatant contaminated with platelets is clear (typically 5-6 washes). The mononuclear cells were then flowed onto a magnetic column using a mononuclear cell isolation kit (Miltenyi Biotec) containing antibodies against non-mononuclear cells, the cells bound to the antibodies were removed, The flow-through is collected and purified from PBMC by negative selection. Mononuclear cells were washed once with wash buffer and inoculated with 100,000 cells per well in 100 μl serum-free RPMI 1640 in a 96-well plate, 5% CO ₂ /95% humidified tissue culture Incubate in an incubator at 37 ° C for 1 hour. After 1 hour, the medium was replaced with 100 μl complete medium (RPMI 1640, 10% human serotype AB (heat inactivated), 25 mM HEPES, 2 mM glutamine, penicillin and streptomycin each 50 U / ml) and overnight ( 16 hours) Incubate.

(Medication regimen)
The next day, the medium is replaced with 100 μl fresh complete medium with or without human β-amyloid 1-42 peptide (5 μM) and incubated for 5 hours at 37 ° C. in a 5% CO ₂ /95% humidified tissue culture incubator. To do. The medium is then removed and discarded. Each well was washed once with Hanks buffered saline (HBSS) containing 1 mM CaCl ₂ and then 80 μl of the HBSS / CaCl ₂ -inhibiting compound of the present invention (for a final concentration of 23 nM and 206 nM, HBSS / CaCl 10x stock in ₂ ) and incubated for 15 minutes in a tissue culture incubator, then either 10 μl HBSS / CaCl ₂ or 10 μl benzoyl ATP (BzATP; 3 mM in HBSS / CaCl _{2 for} a final concentration of 300 μM And incubate for an additional 30 minutes in a tissue culture incubator. The medium is then transferred to a new 96-well plate for storage at -70 ° C until the content is quantified by ELISA (R & D Systems). Cells were washed once with HBSS / CaCl ₂ and then 100 μl ice cold cell lysis buffer (100 mM Tris pH 7.6, 1% Triton X-100, and 30 ml Roche Biochemicals Complete®). Cells are lysed with 1 tablet per 30 ml protease inhibitor). Cell lysates are stored at −70 ° C. until IL-1β is quantified by ELISA.

(Example 6)
(In vivo animal model)
A. This example illustrates the efficacy of the compounds of the present invention in the treatment of multiple sclerosis. As described herein, an experimental autoimmune encephalomyelitis (EAE) model is used to demonstrate such efficacy. The following procedure is used in this model.

(animal)
SJL / J female mice, 8 weeks old, are obtained from Jackson Laboratories.

(antigen)
Myelin proteolipid protein (PLP 139-151) (HSLGKWLGHPDKF) (catalog number H-2478) is available from BACHEM, Bioscience, 3700 Horizon Dr. , King of Prussia, Pa. 19406, 1-610-239-0300 (telephone), 1-610-239-0800 (fax).

  Freund's complete adjuvant H37Ra [1 mg / ml Mycobacterium tuberculosis H37Ra] is obtained from Difco 1-800-521-0851 (catalog number 3114-60-5, 6 × 10 ml).

  Mycobacterium tuberculosis is also obtained from Difco, 1-800-521-0851 (catalog number 3114-33-8, 6.times.100 mg).

(Pertussis toxin)
Bordetella Pertussis (lyophilized powder containing PBS and lactose) is obtained from List Biological Laboratories-1-408-866-6363 (Preparation No. 180, 50 ug).

(Induction of EAE in mice)
PLP139-151 peptide was dissolved in H ₂ O: PBS (1: 1) solution to a concentration of 7.5 mg / 10 ml (75 μg PLP per group) and 40 mg / 10 ml heat-sterilized mycobacterium tuberculosis H37Ra was added Emulsified with the same volume of CFA. 0.2 ml of peptide emulsion is injected subcutaneously into the abdominal side of the mouse (0.1 ml on each side). On the same day and 72 hours later, 100% 35 ng and 50 ng Bordetella Pertussis toxin in saline are injected intravenously, respectively.

(Clinical evaluation)
Stage 0: Normal stage 0.5: Partially dragged stage 1: Completely dragged stage 2: Staged reflex failure Stage 2.5: Lack of directed reflex (not weaker than stage 3)
Stage 3: Partial hind limb paralysis stage 3.5: One limb completely paralyzed, the other limb partially paralyzed Stage 4: Hind limb fully paralyzed stage 4.5: Limb fully paralyzed, Drowning stage 5: Death by EAE (clinical course of EAE)
Acute phase: first clinical attack (days 10-18)
Remission phase: period of clinical improvement after a clinical attack; characterized by a decrease in clinical score (> = 1 grade) for at least 2 days after the peak score of acute phase or disease recurrence.
Recurrence: After reaching remission, the clinical score increases by at least 1 great for at least 2 days.

  Animals treated with the compounds of the invention are generally expected to show improved clinical scores.

  B. This example describes a protocol for measuring the efficacy of a compound of the present invention for the treatment of stroke using an animal model.

Male Sprague Dawley rats (Charles River) weighing 280-320 g are allowed free access to food and water and are allowed to acclimate for a minimum of 4 days prior to use in the experiment. All rats for use in the study are fasted at 3:00 pm the day before surgery, but are allowed free access to water. Prior to surgery, each rat is weighed. Rats are initially introduced with 5% isoflurane (Aerlane, Fort Dodge) combined with 30% O ₂ and 70% N ₂ O for 2-5 minutes. The rat is then placed on a circulating water heating pad and placed in a nose cone for spontaneous breathing of anesthetic gas. Reduce isoflurane to 2%. A rectal thermometer is inserted to maintain body temperature at 36.5-37.5 ° C. The whole surgical site is shaved and then those parts are scrubbed with betadine.

(surgery)
A temporal muscle probe is placed in the right temporal muscle and "brain" temperature "is monitored. A midline neck incision is made in the upper thorax of the rat. Carefully dissect, remove and retract the sternomastomas, digastric and sternohyoid muscles to expose the right common, internal and external carotid arteries. Cut the right common carotid artery with 5-0 silk thread. During the surgery, the thread is loosened to allow reperfusion every 2-4 minutes. The right external carotid artery and superior thyroid artery are also dissected, the superior thyroid artery cauterized, while the external carotid artery is ligated at the periphery using 5-0 silk thread. Tie loosely around the external carotid artery with another 5-0 silk thread. The occipital artery is cut, ligated, and incised. Separate the internal carotid artery.

  With respect to the fixed common external carotid artery, an aneurysm clip is placed in the internal carotid artery. A small incision is made distal to the external carotid artery. A 3-0 nylon thread coated with poly-L-lysine is then inserted from the external carotid artery to the common carotid artery. The 5-0 silk thread loosely tied around the external carotid artery is now lightly tightened around the filament. The external carotid artery is then incised, the remaining part of the external carotid artery with fibers is rotated, and the filament is inserted into the internal carotid artery. The length of insertion depends on body weight and rat pedigree. In Sprague Dawley rats, the monofilament is inserted 18-19 mm (18 mm is for rats with <300 gm body weight and 19 mm is for rats with .300 gm body weight) that effectively blocks blood flow to the central cerebral artery. .

  A PE50 tube for intravenous administration of the compound is inserted into the external jugular vein. The cannula is exposed to the nape of the neck that has previously been shaved and sutured in place. The wound is closed using sutures. During surgery, a catheter is inserted into the right femoral artery for blood gas and glucose measurements.

  Two hours after the insertion of the monofilament suture, the rats are re-anesthetized using the same anesthetic combination originally used and placed in a nose cone with an isofuran concentration reduced to 2%. Open the neck incision again to expose the external carotid artery. Blood flow is restored by completely removing the intraluminal suture from the carotid artery. The incision is then closed with 3-0 silk with intermittent stitches.

(Compound administration)
The above procedure is applied to 5 groups of 15 animals. Following MCAo, the compound is infused (intravenous) at different doses (dose response) for different periods of time. After MCAo, starting at various intervals, a predetermined concentration is injected for a preselected period. Vehicle treated controls are usually given 0.9 ml / hour of infusion. Start the positive control compound simultaneously.

(Neural test)
Prior to surgery, a neurological test is bruised 2 hours after onset of ischemia and 24 hours after ischemia. A posture reflex test designed to evaluate the posture of the upper body is performed with the rat floating on the plane. A normal rat stretches the entire body and both forelimbs towards the plane. Rats with fractures continue to refract the contralateral leg and show signs of body rotation. The rat responds to a gentle lateral push with a finger behind the shoulder. Normal rats resist such push, and rats with fractures do not. The induced forelimb is placed in response to visual and tactile stimulation. The animal supports the body so that the side or back of the forelimb is placed against the bench. This test is repeated, this time blocking the rat's field of view.

  Upon completion of each experiment, all animals were deeply anesthetized with isoflurane (5%), euthanized by decapitation, brain dissection, and the extent and location of ischemic damage was histologically validated with tetrazolium chloride. To do.

  C. In this example, a 2,4-dinitrobenzenesulfonic acid (DNBS) -induced distal colitis model (model of inflammatory bowel disease) is used to illustrate the anti-inflammatory activity of the compounds of the present invention. .

(Test substance and dosing pattern)
The compounds of the invention are dissolved in 2% Tween 80 vehicle in distilled water for oral administration at a dose of 50 mg / kg, and 2% Tween 80 and 0. 0 for intraperitoneal injection at 30 mg / kg. Dissolve in a 9% NaCl vehicle. Administration is performed once a day for 7 consecutive days. The dose is 10 ml / kg. DNBS was performed 2 hours after administration on the second day.

(animal)
In this study, male Wistar, Long Evans rats provided by the Animal Breeding Center of MDS Panlabs Taiwan, and male mice derived from Balb / cByJ, provided by the National Laboratory Animal Breeding Research Center (NALBRC, Taiwan): ± 2 g) can be used. The space area allocation for the six animals is 45 × 23 × 15 cm. Animals were placed in APEC® cages (Allentown Caching, Allentown, NJ.) In a positive pressure isolation incubator (NuAire®, type: Nu-605, airflow rate: 50 ± 5 ft / min, HEPA filter). In the MDS Panlabs Taiwan laboratory in a temperature (22 ° C.-24 ° C.) and humidity (60% -80%) controlled environment with a 12 hour light / dark cycle before use. Maintain for a week. Free access to standard laboratory chow for rats (Fusow Industry, Taiwan) and water is allowed. All aspects of this work, including containment, experimentation and animal disposal, are generally performed in accordance with International Guiding Principles for Biomedical Research Involving (CIOMS Publication No. ISBN92 90360194, 1985).

(chemicals)
DNBS is obtained from TCI, Tokyo, Japan, ethanol is obtained from Merck, Germany, and sulfazine is purchased from Sigma, USA.

(apparatus)
Electronic scale (Tanita, type 1140, Japan), electronic scale (Sartorius, R160P, Germany), glass syringe (2 ml, Mitsuba, Japan), rat oral needle, hypodermic needle (25 G. time. 1 inch TOP) Co., Japan), stainless steel scissors (Klappenclear, Germany), stainless steel scissors (Klappenclear, Germany).

(Method)
A group of 3 Wistar derived male rats weighing 180 ± 20 g is used. Distal colitis is induced by internal colon instillation of DNBS (2,4-dinitrobenzenesulfonic acid, 30 mg in 0.5 ml of ethanol 30%), after which 2 ml of air is gently injected through the cannula, Ensure that the solution remains in the large intestine. The test substance is administered orally (PO) at a dose of 50 mg / kg or intraperitoneally (IP) at 30 mg / kg once a day for 7 consecutive days. Two hours after dosing on day 2, DNBS is injected into the distal colon of each animal. The control group is treated the same way with vehicle alone and sulfasalazine (300 mg / kg, PO) is used as the control drug. The animals are fasted 24 hours prior to DNBS administration, sacrificed 24 hours after the final treatment, and each large intestine is excised and weighed. During the experiment, the presence of diarrhea is recorded daily. If the abdominal cavity is open before separating the large intestine, describe the adhesion between the large intestine and other organs. After measuring the weight of the large intestine, the extent of the large intestine ulcer is observed and described. The ratio of colon weight to body weight is then calculated for each animal with the formula: colon (g) / BW × 100%. The “net” increase in the ratio of vehicle-control + DNBS group to vehicle-control group is used as a reference value for comparison with the test substance-treated group and is expressed as a% decrease in inflammation. A decrease greater than 30 percent (30%) in the ratio of body weight to “net” colon in each test substance treated group relative to the “net” vehicle + DNBS treated group is considered significant.

  D. In this example, a model of carrageenan-induced edema (inflammatory model, carrageenan) is used to illustrate the anti-inflammatory activity of the compounds of the invention.

(Test substance and dosing pattern)
Compounds of the invention are dissolved in 2% Tween 80 / 0.9% NaCl vehicle and administered intraperitoneally at a dose of 30 mg / kg 30 minutes prior to carrageenan (1% 0.1 ml / limb) administration. . The dose is 10 ml / kg.

(animal)
Animals are prepared according to the procedure described in the previous examples.

(chemicals)
Carrageenan is obtained from TCI, Japan, pyrogen-free saline is obtained from Astar, Taiwan, and aspirin is purchased from ICN BioMedicals, USA.

(apparatus)
Glass syringe (1 ml and 2 ml, Mitsuba, Japan), hypodermic needle 24G × 1 inch (Top Corporation, Japan), intravascular blood meter (intravascular blood meter) # 7150 (UGO Basile, Italy), water Cell (Water cell), diameter 25 mm, # 7157 (UGO Basile, Italy).

(Method)
Long Evans-derived males fasted overnight with test substance (Examples) weighing 150 ± 20 g 30 minutes prior to right hind limb injection of carrageenan (0.1 ml 1% suspension limb subcutaneous) A group of rats is administered IP (30 mg / kg). After carrageenan administration, hindlimb edema is recorded using an intravascular blood flow meter (Ugo Basile catalog number 7150) equipped with a water cell (25 mm diameter, catalog number 7157) as measured by inflammation. A reduction in hind limb edema greater than 30 percent (30%) indicates significant acute anti-inflammatory activity.

  E. This example illustrates the anti-inflammatory activity of the compounds of the present invention using a model of Balb / c mice that have undergone monoclonal antibody (mAb) type II collagen-induced arthritis.

(Test substance and dosing pattern)
The compound of the present invention is dissolved in a vehicle of 2% Tween 80 / 0.9% NaCl at a dose of 50 or 30 and injected orally once a day for 3 consecutive days after injection of a monoclonal antibody of collagen ( 50 mg / kg) or 30 mg / kg. The dose is 20 ml / kg.

(animal)
Animals are prepared according to the procedure described in the previous examples.

(chemicals)
Lipopolysaccharide is obtained from Sigma, USA, indomethacin is obtained from Sigma, USA, Arthrogen-CIA® monoclonal antibodies D8, FlO, DI-2G and A2 are obtained from IBL, Japan, phosphate buffered Saline is purchased from Sigma, USA, and Tween 80 is purchased from Wako, Japan.

(apparatus)
Intravascular blood flow meter (Ugo Basile, Italy) and water cell (Ugo Basile, Italy)
(Method)
Arthritis is induced with a monoclonal antibody (mAbs) in response to type II collagen + lipopolysaccharide (LPS) using a group of 5 Balb / cByJ mice, 6-8 weeks old. Animals are administered intravenously on day 0 with a combination of 4 different monoclonal antibodies at a total dose of 4 mg / mouse, followed 72 hours later (day 3) by intravenous injection of 25 μg LPS. From day 3 one hour after LPS administration, ML-659 is 50 mg / kg (PO) or 30 mg / kg (IP), and vehicle (2% Tween 80 / 0.9% NaCl, PO), and positive As a control, indomethacin 3 mg / kg (PO) is administered once a day for 3 consecutive days. Intravascular blood flow meter (Ugo Basile catalog number 7150) with water cell (diameter: 12 mm) to measure the volume increase of two hind limbs on days 0, 5, 7, 10, 14 and 17 Used for. The% inhibition of volume increase is calculated with the following formula:
Inhibition (%): [1- (Tn-To) / (Cn-Co)] × 100
(Where
Co (Cn): Volume on Day 0 (n) in Vehicle Control To (Tn): Volume on Day 0 (n) in Test Compound Treatment Group)
A greater than 30% reduction in both of the two hindlimb edemas is considered significant.

(Example 7)
(Neuropathic pain model)
In this example, the sciatic nerve ligation model of mononeuropathic pain is used to illustrate the analgesic activity of the compounds of the present invention.

(Test system)
Adult male Sprague Dawley (SD) rats (Charles River Laboratories, San Diego, Calif.) Weighing 250-300 g are used. The animal room is artificially illuminated with a 12-hour light-dark cycle (7:00 AM to 7:00 PM) and has free access to water and food. Animals are randomly assigned to groups.

(Model induction)
Sciatic nerve ligation (SNL, Seltzer model):
Selective nerve injury is created by tightly ligating selected portions of the total sciatic nerve according to Seltzer's method (1990) under anesthesia and aseptic manipulation with pentobarbital (50 mg / kg, ip). Briefly, the left sciatic bone after skin incision and muscle blunt separation at a site near the trochanter just along the point where the posterior biceps half-tendonoid nerve branches from the whole sciatic nerve The high-high level of the nerve is exposed. The nerve is then fixed in this position by being careful not to press the nerve against the underlying structure, and pinching with a fine tweezer sandwiching the epithelium on the dorsal side. 8-0 siliconized silk thread is inserted into the nerve using a reverse-cutting mini-needle with a 3/8 curve, and the back 1/3 to 1/2 of the nerve is the ligature. Tightly ligate to be captured. The muscles are sutured in layers and the skin is closed with wound clips. The animals are then returned to their home gauge. Rats that exhibit post-operative neuroleptic syndrome or poor grooming are removed from the experiment.

(apparatus)
The following equipment is used in this test. Von Frey fiber set (Touch-test Sensitivity Evaluator, North Coast Medical, Morgan Hill, CA)
Statistical methods:
Within each experiment, mean, standard error (SEM) and statistical significance are calculated with Microsoft Excel® using mean, standard error and uncontrasted two-tailed t-test function, respectively. . Statistical significance of effects observed in individual experiments is measured using Prism (GraphPad Software, San Diego, Calif.) And determined with a one-way or two-way analysis of variance (ANOVA) function. Statistical analysis is performed with a confidence limit of 0.95 and a significance level of 0.05.

(Example 8)
(Pore formation)
THP-1 cells (ATCC catalog number 285-IF-100) are plated in a 96-well plate at a concentration of 200,000 cells per well, 10% FBS, 100 IU / mL penicillin, 100 ug / mL Differentiation in RPMI-1640 medium (ATCC catalog no. 30-2001) containing 100 ng / mL LPS and 100 ng / mL IFN-γ. After differentiation, cells are pretreated with RPMI-1640 medium containing 100 IU / mL penicillin, 100 ug / mL streptomycin, using an appropriate concentration of the compound of interest for 30 minutes. The pre-treated medium is then assayed (20 mM HEPES, 10 mM d-glucose, 118 mM NMDG, 5 mM) containing 5 uM Yo-Pro1 (Molecular Probes Cat # Y3603) and the appropriate concentration of the compound of interest. KLCl, 0.4 mM CaCl ₂ ) and incubate the cells for an additional 10 minutes. 2 ', 3'-O- (4-benzoylbenzoyl) -adenosine 5'-triphosphate (Sigma Aldrich catalog number B6396) was then added to a final concentration of 40 uM and the fluorescence intensity reading was taken from a Tecan Satire plate reader. And measure every minute for 50 minutes at 491/509 excitation / emission. During this time, the temperature is maintained at 37 ° C. Background adjusted to the fluorescence intensity level between drug-treated and non-treated cells is used to calculate% inhibition.

Example 9
(IL-1β release assay)
THP-I cells (ATCC catalog number 285-IF-100) are plated in a 96-well plate at a concentration of 200,000 cells per well, 10% FBS, 100 IU / mL penicillin, 100 ug / mL. Differentiation in RPMI-1640 medium (ATCC catalog no. 30-2001) containing 100 ng / mL LPS and 100 ng / mL IFN-γ. After differentiation, cells are treated with RPMI-1640 medium containing 100 IU / mL penicillin, 100 ug / mL streptomycin and 100 ng / mL fresh LPS for an additional 2 hours. Cells are then pretreated for 30 minutes with the appropriate concentration of the compound of interest in RPMI medium containing 100 IU / mL penicillin and 100 ug / mL streptomycin. After pretreatment, 2 ′, 3′-O- (4-benzoylbenzoyl) -adenosine 5′-triphosphate (Sigma Aldrich catalog number B6396) is added to a final concentration of 250 uM and the cells are incubated for an additional 45 minutes. 30 uL of cell supernatant is then collected and IL-1β levels are measured by ELISA (R & D systems catalog number HSLB50) using a Tecan Safe plate reader according to the manufacturer's recommendations. Background adjusted to IL-1β levels of drug-treated and non-treated cells is used to calculate% inhibition.

  The synthetic and biological examples described in this application are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any way. In the examples, all temperatures are in degrees Celsius unless otherwise noted. The compounds prepared according to the present invention are shown in the table below along with their biological activity data. The synthesis of these representative compounds is performed according to the method described above.

(Exemplary Compounds of the Invention)
The following compounds are or can be prepared according to the synthetic methods described herein for Example Methods AK. With respect to Table 1 below, the activity of each compound, which can be measured using the IL-1β assay method described in Example 9, is expressed as follows:
“+” Compound showing inhibition of 0-25% at 0.3 μM concentration “++” Compound showing inhibition of 26-50% at 0.3 μM concentration “++” Compound showing 51-75% inhibition at 0.3 μM concentration “++++” Compound “*” showing inhibition of 76% or more at 0.3 μM concentration Compound “**” showing inhibition of 0 to 25% at 0.1 μM concentration 26 to 50% inhibition at 0.1 μM concentration Compound “***” Compound “***” showing inhibition of 51 to 75% at 0.1 μM concentration Compound “+++” or “***” showing inhibition of 76% or more at 0.1 μM concentration The compounds with the indicated% inhibition are of interest.

  Table 1: IL-1β% inhibition of exemplary compounds

（ＩＣ_５０測定）
本明細書に記載される細胞モデルにおいて、表１に記載された化合物の活性を試験した。具体的には、前記実施例９のように、細胞を異なる量の試験中の化合物で前処理し、放出されたＩＬ−１βを測定した。測定を行い、以下の表２に示されたＩＣ_５０値は、ＧｒａｐｈＰａｄ Ｐｒｉｓｍソフトウェア（ＧｒａｐｈＰａｄ Ｓｏｆｔｗａｒｅ社）を使用して、データを、４パラメータロジスティック方程式にフィッティングすることによって計算した。方程式は、以下の式で表わされる：
Ｙ＝ボトム＋（トップ−ボトム）／（１＋１０＾（（ＬｏｇＥＣ５０−Ｘ）^＊ヒルスロープ））
（式中、Ｘは濃度の対数であり、Ｙはその応答であり、Ｙはボトムから出発し、Ｓ字曲線を描きトップに到達する）
（表２：例示的な化合物のＩＬ−１βＩＣ_５０）

(IC ₅₀ measurement)
The activity of the compounds described in Table 1 was tested in the cell model described herein. Specifically, as in Example 9, cells were pretreated with different amounts of the compound under test and the released IL-1β was measured. Measurements were made and the IC ₅₀ values shown in Table 2 below were calculated by fitting the data to a 4-parameter logistic equation using GraphPad Prism software (GraphPad Software). The equation is represented by the following formula:
Y = bottom + (top-bottom) / (1 + 10 ^ ((LogEC50-X) ^* hill slope))
(Where X is the logarithm of concentration, Y is the response, Y starts from the bottom, draws an S-curve and reaches the top)
Table 2: IL-1β IC ₅₀ of exemplary compounds

（ヒト肝臓ミクロソームにおける半減期（ＨＬＭ））
試験化合物（１μＭ）を、９６ディープウェルプレートで、１００ｍＭリン酸カリウム緩衝液（ｐＨ７．４）中の３．３ｍＭのＭｇＣｌ_２および０．７８ｍｇ／ｍＬのＨＬＭ（ＨＬ１０１）と一緒に、３７℃でインキュベートする。反応混合物を、２つの群、非Ｐ４５０群およびＰ４５０群に分ける。ＮＡＤＰＨを、Ｐ４５０群の反応混合物にだけ添加する。Ｐ４５０群の試料のアリコートを、０、１０、３０および６０分の時点で集める。ここで、０分の時点とは、ＮＡＤＰＨをＰ４５０群の反応混合物に添加した時点を示す。非Ｐ４５０群の試料のアリコートを、−１０分および６５分の時点で集める。集めたアリコートを、内部標準を含むアセトニトリル溶液で抽出する。析出したタンパク質を、遠心分離機（２０００ｒｐｍ、１５分）で沈降させる。上清の化合物濃度を、ＬＣ／ＭＳ／ＭＳシステムで測定する。

(Half life in human liver microsomes (HLM))
Test compound (1 μM) is added to a 96 deep well plate at 37 ° C. with 3.3 mM MgCl ₂ and 0.78 mg / mL HLM (HL101) in 100 mM potassium phosphate buffer (pH 7.4). Incubate. The reaction mixture is divided into two groups, a non-P450 group and a P450 group. NADPH is added only to the reaction mixture of the P450 group. Aliquots of P450 group samples are collected at 0, 10, 30 and 60 minutes. Here, the time point of 0 minutes indicates the time point when NADPH was added to the reaction mixture of the P450 group. Aliquots of non-P450 group samples are collected at -10 and 65 minutes. Collected aliquots are extracted with an acetonitrile solution containing an internal standard. The precipitated protein is precipitated with a centrifuge (2000 rpm, 15 minutes). The compound concentration in the supernatant is measured with an LC / MS / MS system.

Half-life values are obtained by plotting the natural log of the compound / internal standard peak area ratio versus time. The slope of the best fit line through the points gives the rate of metabolism (k). This is converted to a half-life value using the following equation:
Half-life = ln2 / k
(Pharmacokinetic evaluation of compounds after intravenous and oral administration in rats)
Male Sprague Dawley rats are acclimated for at least 24 hours before beginning the experiment. During the acclimatization period, all animals have free access to food and water. However, at least 12 hours before the start of the experiment, food is removed from the animal's gauge, but water is not removed. During the first 3 hours of the experiment, animals have free access to water only. Each of at least 3 animals will be tested for intravenous and oral administration. For formulations for intravenous injection, the compound is dissolved in a mixture of 3% (w / v) dimethyl sulfoxide, 40% (w / v) PEG400 and the remaining 40% (w / v) Captisol in water (0. 25-1 mg / mL). Animals are weighed before dosing. The measured body weight is used to calculate the dose for each animal.
Dose (mL / kg) = 1 mg / kg / Prescription concentration (mg / mL)
If the formulation concentration is less than 0.5 mg / mL, the dosage is about 2 mL / kg.

For oral formulations, a compound of the invention is suspended in a mixture of 5% (w / v) 10% (v / v) Tween 80 in water and 95% (w / v) 0.5% methylcellulose in water. (0.5-0.75 mg / mL). PO rats are usually administered by oral gavage according to the same dosage regime as IV to achieve a dose concentration of 1-5 mg / kg. For IV administration, blood samples are collected (using pre-heparinized syringes) via the jugular vein catheter 2, 5, 15, 30, 60, 120, 180, 300, 480 and 1440 minutes after administration. . For PO administration, blood samples are collected via the jugular vein catheter before administration and at 5, 15, 30, 60, 120, 180, 300, 480 and 1440 minutes (using a pre-heparinized syringe). ). Approximately 250 uL of blood is obtained from the animals at each time point. Replace with 0.9% normal saline in the same volume to prevent dehydration. Whole blood samples are kept on ice until centrifugation. The blood sample is then centrifuged at 14,000 rpm for 10 minutes at 4 ° C. and the upper plasma layer is transferred to a clean vial and stored at −80 ° C. The resulting plasma sample is then analyzed by liquid chromatography-tandem mass spectrometry. After measurement of the plasma sample and dosing solution, the plasma concentration-time curve is plotted. Plasma exposure is calculated as the area under the concentration-time curve inserted at time infinity (AUC _inf ). AUC _inf is averaged and calculated as follows for oral bioability (% F) for individual animals:
AUC _inf (PO) / AUC _inf (IV), normalized to individual dose concentrations.
% F may be reported as the average% F of all animals that were orally administered a particular concentration of the compound of the invention.

  From the foregoing description, various modifications and alterations will occur to those skilled in the art in the compositions and methods of the invention. All such modifications that fall within the scope of the appended claims are intended to be included herein.

  All publications cited in this specification, including but not limited to patents and patent applications, are individually incorporated by reference as if each individual publication were specifically and independently described in full. Which is hereby incorporated by reference as indicated.

  The chemical names of the compounds of the present invention given in this application are not verified using the Open Eye Software's Lexichem naming tool, Symyx Renaissance Software's Reaction Planner, or MDL's ISIS Draw Autonomous Software tool. .

Claims (73)

formula:

(Where
B and Y are independently selected from CR ^2a and CR ^2a R ^2b ;
W, W ′ and Z are independently selected from CR ⁴ and N, provided that all three of W, W ′ and Z are not N at the same time;
L ¹ is a substituted or unsubstituted C ₁ -C ₅ alkylene;
n is 1 or 2;
R ¹ is selected from a substituted or unsubstituted aryl ring and a substituted or unsubstituted heteroaryl ring;
Each of R ^{2 ′} and R ^{2 ″} is independently selected from hydrogen, halo, and substituted or unsubstituted C ₁ -C ₆ alkyl;
R ³ is hydrogen or an alkyl, dialkylamino, acyloxy, alkoxy, -SO 2 _- Ri alkyl, substituted or unsubstituted aryl, heteroaryl, functional groups der selected from cycloalkyl or cycloheteroalkyl, wherein “Substitution” for the R ³ moiety refers to a group in which each of one or more hydrogen atoms is independently replaced with the same or different substituent (s), such as halo, alkyl, aryl, arylalkyl, cycloalkyl, cyclo heteroalkyl, heteroalkyl, heteroaryl, ^{heteroarylalkyl, -O -, = O, -OR} 46, -SR 46, -S -, = S, -NR 46 R 47, = NR 46, -CF 3, - _{CN, -OCN, -SCN, -NO,} -NO 2, = N 2, -N 3, -S (O) 2 O -, -S ( _{^{) 2 R 46, -OS (O}} 2) O -, -OS (O) 2 R 46, -P (O) (O -) 2, -P (O) (OR 46) (O -), - C (S) OR ⁴⁶ , —NR ⁴⁸ C (O) NR ⁴⁶ R ⁴⁷ , —NR ⁴⁸ C (S) NR ⁴⁶ R ⁴⁷ , —NR ⁴⁹ C (NR ⁴⁸ ) NR ⁴⁶ R ⁴⁷ and —C (NR ⁴⁸ ) NR ⁴⁶ R ^47, wherein R ⁴⁶ , R ⁴⁷ , R ⁴⁸ and R ⁴⁹ are each independently alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl. Substitution with a substituent selected from the group consisting of :
R ⁴ is independently H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxy Carbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or Unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfate ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, Carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted hetero Selected from aryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro and thio;
(The dotted bond is a single bond or a double bond)
Or a pharmaceutically acceptable salt or solvate thereof, and stereoisomers, isotopic variants and tautomers thereof. Each of B and Y ^{is CR} 2a ^{R 2b;} and the binding of the dotted line is a single bond, A compound according to claim 1. The compound of claim 1, wherein each of B and Y is CH ₂ ; and the dotted bond is a single bond. The compound of claim 1, wherein each of B and Y is CR ^2a ; and the dotted bond is a double bond. The compound of claim 1, wherein each of B and Y is CH; and the dotted bond is a double bond. The compound of claim 1, wherein each of R ^{2 ′} and R ^{2 ″} is H. The compound of claim 1, wherein one of R ^{2 ′} and R ^{2 ″} is independently Me and the other is H. The compound of claim 1, wherein each of R ^{2 ′} and R ^{2 ″} is Me. The compound according to claim 1, wherein n is 1. R ¹ is a substituted or unsubstituted aryl, The compound of claim 1. The compound according to claim 1, wherein R ¹ is substituted or unsubstituted phenyl. The compound according to claim 1, wherein R ¹ is substituted or unsubstituted naphthyl. The compound of claim 1, wherein R ¹ is substituted or unsubstituted heteroaryl. The compound of claim 1, wherein R ¹ is substituted or unsubstituted pyridyl. The compound according to claim 1, wherein R ¹ is a substituted or unsubstituted quinoline. The compound according to claim 1, wherein R ¹ is substituted or unsubstituted benzodioxole, benzodioxan, benzofuran, benzothiophene, or benzodioxepin. Said compound is of formula III or IV:

(Where
W is CR ⁴ ; Z is CR ⁴ ;
L ¹ , R ¹ , R ^{2 ′} , R ^{2 ″} , R ³ and R ⁴ are as in claim 1;
R ⁵ is H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxy Carbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl Substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfate ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, azide, carbo Xyl, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, Selected from substituted or unsubstituted heteroalkyl, hydroxy, nitro and thio)
Or a pharmaceutically acceptable salt or solvate thereof, and stereoisomers, isotopic variants and tautomers thereof. The compound of claim 17, wherein each of R ^{2 ′} and R ^{2 ″} is H. 18. A compound according to claim 17, wherein R2 ^' is Cl or F; and R2 ^" is H. The compound of claim 17, wherein R ^{2 ′} is Me; and R ^{2 ″} is H. 18. A compound according to claim 17, wherein R < ₁ > is selected from substituted or unsubstituted phenyl. 18. A compound according to claim 17, wherein R < ₁ > is selected from substituted or unsubstituted naphthalene. The compound is of formula VI or VII:

(Where
W is CR ⁴ ; Z is CR ⁴ ;
L ¹ , R ¹ , R ^{2 ′} , R ^{2 ″} , R ³ and R ⁴ are as in claim 1; R ⁵ is as in claim 17;
Each R ^4a is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, aryloxy, alkoxy Carbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or Unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfate ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphos Holyl, azide, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted Selected from heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro and thio; m is selected from 0 to 5)
Or a pharmaceutically acceptable salt or solvate thereof, and stereoisomers, isotopic variants and tautomers thereof. 24. The compound of claim 23, wherein each of R ^{2 ′} and R ^{2 ″} is H. 24. The compound of claim 23, wherein R2 ^' is Cl or F; and R2 ^" is H. 24. The compound of claim 23, wherein R2 ^' is Me or Et; and R2 ^" is H. Said compound is of formula IX or X:

(Where
W is CR ⁴ ; Z is CR ⁴ ;
L ¹ , R ³ and R ⁴ are as in claim 1; R ⁵ is as in claim 17; m and R ^4a are as in claim 23; R ^{2 ′} is H Or Me;
Each R ^4b is independently selected from C ₁ -C ₄ alkyl and hydroxy)
Or a pharmaceutically acceptable salt or solvate thereof, and stereoisomers, isotopic variants and tautomers thereof. 28. A compound according to any of claims 23 or 27, wherein m is 1, 2 or 3. 28. A compound according to any of claims 23 or 27, wherein m is 1. Each R ^4a is independently Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF ₃ , CHF ₂ , OCF ₃ , i-Pr, i-Bu, _{t-Bu, SMe, CH =} CH-CO 2 H, sOMe, SO 2 Me, SO 3 H, is selected from _SO 3 Me and pyridyl a compound according to any one of claims 23 or 27. L ¹ _is a C 1 -C ₅ alkylene group, the compound according to any one of claims 1 to 30. L ¹ is either unsubstituted or alkyl and C ₁ -C ₅ alkylene substituted with one or more substituents selected from oxo, according to any one of claims 1 to 30 Compound. R ³ is alkyl, dialkylamino, acyloxy, alkoxy and -SO ₂ - is selected from alkyl, A compound according to any one of claims 1 to 32. R ³ _{is, t-Bu, NMe2, SO} 2 Me, selected from OMe and OCOMe, compounds according to any one of claims 1 to 32. R ³ is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl or cycloheteroalkyl A compound according to any one of claims 1 to 32. The compound according to any one of claims 1 to 32, wherein R ³ is substituted or unsubstituted phenyl, pyridyl, pyran, tetrahydropyran, piperidine, morpholine, pyrrolidine, pyridinone or benzodioxane. The group -L ₁ -R ³ is

31. A compound according to any one of claims 1 to 30, selected from: 38. The compound of any one of claims 1-37, wherein R2 ^' is Me. 38. The compound according to any one of claims 1-37, wherein R2 ^' is H. Said compound has the formula: XIa, XIb, XIc, XId, XIe, XIf, XIg, XIh or XIj:

Wherein m and R ^4a are as in claim 23; R ⁵ is selected from H, alkyl or halo
The compound of Claim 1 represented by these. 41. The compound of claim 40, wherein m is 1, 2 or 3. 41. The compound of claim 40, wherein m is 1 or 2. 41. The compound of claim 40, wherein m is 2. Each R ^4a is independently Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF ₃ , CHF ₂ , OCF ₃ , i-Pr, i-Bu, _{t-Bu, SMe, CH =} CH-CO 2 H, SOMe, SO 2 Me, SO 3 H, is selected from _SO 3 Me, and pyridyl compound according to any one of claims 41 to 43. m is 1, and ^{R 4a} is CF _3, A compound according to any one of claims 41 to 43. m is 2 and the ^{R 4a} is F and CF _3, A compound according to any one of claims 41 to 43. 44. The compound according to any one of claims 41 to 43, wherein m is 2 and ^R4a is F and Cl. W is CR ^4, A compound according to any one of claims 1 to 16. 40. A compound according to any one of claims 1 to 39 wherein each of W and Z is independently CH. The compound according to any one of claims 1 to 16, wherein W is N. 17. A compound according to any one of claims 1 to 16, wherein W is N and Z is CH. R ⁵ is H, A compound according to any one of claims 17 to 49. 2. The compound of claim 1, wherein the compound is selected from the compounds listed in Table 1. 54. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of any of claims 1-53. 55. The pharmaceutical composition according to claim 54, wherein the carrier is a parenteral carrier. 55. The pharmaceutical composition according to claim 54, wherein the carrier is an oral carrier. 55. The pharmaceutical composition according to claim 54, wherein the carrier is a topical carrier. A disease or condition abnormal activation of P2X ₇ receptors in vivo relevant as the cause, prevention in a mammal, a composition for treating or ameliorating the composition, effective to treat the disease 54. A composition comprising a compound according to any of claims 1 to 53 in an amount effective to treat the amount or condition. 59. The composition of claim 58, wherein the disease or condition is a pain state. 59. The composition of claim 58, wherein the disease or condition is an autoimmune disease. 59. The composition of claim 58, wherein the disease or condition is an inflammatory disease or inflammatory condition. 59. The composition of claim 58, wherein the disease or condition is a neurological or neurodegenerative disease or condition. Acute pain, inflammatory pain and neuropathic pain, chronic pain, toothache and pain including migraine, headache including cluster headache and tension headache, Parkinson's disease, multiple sclerosis; neuroinflammation, traumatic brain injury and encephalitis Diseases and disorders mediated by or resulting in them; centrally mediated neuropsychiatric diseases and disorders, manic depression, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognitive disorders; epilepsy And seizure disorders; prostate dysfunction, bladder dysfunction and bowel dysfunction, urinary incontinence, dysuria, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and respiratory tract diseases and disorders, allergies Rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; mediated by inflammation, arthritis, rheumatoid arthritis and osteoarthritis Diseases and disorders that cause or cause them, myocardial infarction, various autoimmune diseases and autoimmune disorders, uveitis and atherosclerosis; itching / pruritus, psoriasis; obesity; lipid disorders; cancer; blood pressure; And a composition for preventing, treating, or ameliorating a disease or condition selected from renal dysfunction in a mammal, in an amount effective to treat the disease or condition. 54. A composition comprising the compound according to any one of claims 1 to 53. 64. The composition of claim 63, wherein the disease or condition is Parkinson's disease. 64. The composition of claim 63, wherein the disease or condition is rheumatoid arthritis. 64. The composition of claim 63, wherein the disease or condition is traumatic brain injury. 64. The composition of claim 63, wherein the disease or condition is osteoarthritis. 64. The composition of claim 63, wherein the disease or condition is pain. 64. The composition of claim 63, wherein the disease or condition is neuropathic pain. Symptoms of exposure to capsaicin, symptoms of burns or irritation due to exposure to heat, symptoms of burns or irritation due to exposure to light, symptoms of burns, bronchoconstriction or irritation due to exposure to tear gas, and exposure to acids A composition for treating a mammal suffering from at least one symptom selected from the group consisting of symptoms of burns or irritation, said composition comprising an effective amount or condition for treating a disease 54. A composition comprising an amount of a compound according to any of claims 1-53 in an effective amount for treatment. The pain is post-mastectomy pain syndrome, stump pain, phantom limb pain, oral neuropathic pain, Charcot pain, toothache, toxic snake bite, spider bite, insect bite, postherpetic neuralgia, diabetic neuropathy, Reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barre syndrome, sensory abnormal femoral neuralgia, oral burning sensation syndrome, bilateral peripheral neuropathy, burning pain Sciatica, peripheral neuritis, polyneuritis, segmental neuritis, gombo neuritis, neuritis, cervical neuralgia, cranial neuralgia, facial neuralgia, glossopharyngeal neuralgia, myalgia, idiopathic neuralgia, intercostal neuralgia , Breast neuralgia, temporomandibular neuralgia, Morton neuralgia, rhinocephalic neuralgia, occipital neuralgia, erythema, slader neuralgia, splenic palate neuralgia, supraorbital neuralgia, vidian neuralgia, sinusitis headache, Zhang headache, labor, childbirth, intestinal gas, menstruation, associated with a condition selected from the group consisting of cancer and trauma, composition according to claim 70. 54. A composition comprising a compound according to any one of claims 1 to 53 for use as a formulation. Acute pain, inflammatory pain and neuropathic pain, chronic pain, toothache and pain including migraine, headache including cluster headache and tension headache, Parkinson's disease, multiple sclerosis; neuroinflammation, traumatic brain injury and encephalitis Diseases and disorders mediated by or resulting from them; centrally neuropsychiatric diseases and disorders, manic depression, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognitive disorders; prostate Dysfunction, bladder and bowel dysfunction, urinary incontinence, dysuria, rectal hypersensitivity, fecal incontinence, benign prostatic hyperplasia and inflammatory bowel disease; respiratory and respiratory tract diseases and disorders, allergic rhinitis, asthma and reactions Airway disease and chronic obstructive pulmonary disease; mediated by or resulting in inflammation, arthritis, rheumatoid arthritis and osteoarthritis Diseases and disorders, myocardial infarction, various autoimmune diseases and autoimmune disorders, uveitis and atherosclerosis; itching / pruritus, psoriasis; obesity; lipid disorders; cancer; blood pressure; 54. Use of a compound according to any of claims 1 to 53 in the manufacture of a medicament for the treatment or prophylaxis of a spinal cord injury state associated with: a disease or condition selected from renal dysfunction.